In 1545, people throughout central Mexico began dying from a mysterious illness that seemed determined to inflict as much suffering as possible before finishing the job. Victims developed raging fevers and excruciating headaches. Their tongues turned black. Some suffered violent stomach pains, delirium, and seizures. Blood poured from their noses, mouths, and sometimes their eyes. Within three or four days, many were dead.

And things were about to get much worse.

Over the next several years, the epidemic would devastate Indigenous communities across Mexico. Some historical estimates place the death toll as high as 15 million, potentially representing up to 80% of the Indigenous population in affected regions. Entire communities were destroyed, survivors struggled to bury their dead, and the best medical minds of the sixteenth century had no idea what was killing everybody.

That last point deserves some perspective. Sixteenth-century physicians were still operating in a medical profession that considered bloodletting an excellent treatment for practically everything. Nevertheless, even they recognized that this was something extraordinary. Whatever was sweeping through Mexico was unlike the familiar diseases they had encountered.

The epidemic became known as cocoliztli, a Nahuatl word associated with sickness and pestilence. It remains one of the most devastating and mysterious epidemics in recorded history, although it rarely receives the attention given to the Black Death or the great influenza pandemics.

Nearly five centuries later, scientists examining the teeth of people who died during the epidemic discovered evidence that may help identify the killer. An even more surprising genetic discovery suggests that the catastrophe may have left traces in the descendants of those who survived.

It’s a medical mystery that begins with millions of deaths, continues through centuries of uncertainty, and eventually finds investigators questioning witnesses who have been dead for almost 500 years. Remarkably, some of those witnesses still have something to tell us.

Mexico in 1545: A Disaster Already in Progress

To understand the catastrophe of 1545, we need to go back another quarter-century, to a time when the Indigenous peoples of Mexico were already experiencing an upheaval that would fundamentally change their world.

In 1519, Spanish conquistador Hernán Cortés arrived in Mexico, where he encountered the powerful Mexica Empire, commonly known as the Aztec Empire. The Mexica ruled an extensive network of tributary communities from their magnificent capital, Tenochtitlan. Cortés, who had arrived with a comparatively small Spanish force, entered into alliances with Indigenous peoples who had their own reasons for opposing Mexica rule.

The resulting conflict involved armies, political intrigue, sieges, shifting alliances, and the kind of diplomatic maneuvering that generally ends with somebody losing a kingdom. It also introduced a particularly dangerous participant into the proceedings: smallpox.

The virus reached central Mexico in 1520 and spread through populations with no previous exposure to the disease. Smallpox killed enormous numbers of people, including the Mexica ruler Cuitláhuac. When Tenochtitlan finally fell in August 1521, the conquest had been accomplished through a combination of military force, Indigenous alliances, political divisions, and a devastating epidemic.

The arrival of European diseases would continue to have catastrophic consequences. As explored in our examination of ten illnesses that changed history, microorganisms have an unfortunate habit of influencing political developments without bothering to consult generals, kings, or other people who consider themselves important.

By 1545, the surviving Indigenous communities were living under Spanish colonial rule. Warfare, displacement, forced labor, tribute demands, and food insecurity had already weakened many communities. Then a new epidemic arrived, and the suffering that followed was unlike anything they had experienced before.

The conquest had ended more than two decades earlier. The demographic catastrophe, however, was still gathering momentum.

What Was Cocoliztli?

The Indigenous population referred to the mysterious sickness as cocoliztli, a word from Nahuatl, the language spoken by the Mexica and many other peoples of central Mexico. It can be translated broadly as sickness, pestilence, or epidemic. The particularly devastating outbreak was also described as hueycocoliztli, meaning the great pestilence or great sickness.

This presents modern medical investigators with an immediate problem. Cocoliztli wasn’t necessarily the name of one specific disease. It was a description of what people were experiencing. Trying to identify a pathogen solely from that name is rather like asking someone what killed an entire village and receiving the answer, “Something dreadful.”

Accurate, perhaps, but diagnostically unhelpful.

The symptoms recorded during the great epidemics were terrifying. Patients suffered high fevers, intense thirst, severe headaches, dizziness, abdominal pain, diarrhea, and jaundice, which caused their skin and eyes to turn yellow. Some developed painful swellings around their ears and necks. Others became delirious or experienced convulsions.

Perhaps the most disturbing symptom was bleeding. Blood could emerge from the nose, mouth, ears, and other parts of the body. Some accounts described discolored urine and severe internal damage. In fatal cases, the disease could progress from the first symptoms to death in only a few days.

These descriptions come from several historical accounts, particularly those of the 1576 epidemic. We cannot assume every victim in 1545 experienced exactly the same symptoms or that every outbreak described as cocoliztli had an identical cause. That’s one of the complications in reconstructing the history.

Nor did the disease affect every population equally. Historical observers reported that Indigenous communities suffered disproportionately, while Spaniards generally experienced much lower mortality. The difference may have involved previous exposure to particular pathogens, differences in living conditions, nutritional status, labor demands, or other factors that cannot now be disentangled with certainty.

Whatever the explanation, the disparity was horrifying. For communities already struggling to survive under colonial rule, the epidemic threatened not merely individual lives but the continued existence of entire settlements.

The Epidemic That Killed Millions

How many people died in the cocoliztli epidemic? The answer depends upon which historical population estimates you accept, and estimating the population of sixteenth-century Mexico is not an exercise for anyone who becomes emotionally attached to a single number.

There was no modern national census. Records were incomplete, communities were scattered across an enormous territory, and the upheaval of conquest made demographic reconstruction especially difficult. Historians have spent generations attempting to calculate how many Indigenous people lived in Mexico before European contact and how rapidly that population declined.

Some widely cited estimates place the death toll from the 1545–1548 epidemic between five million and fifteen million people. Under particular demographic reconstructions, this may have amounted to as much as 80% of the remaining Indigenous population. The upper figure is an estimate, not a verified body count, and should not be mistaken for proof that 80% of everyone living within modern Mexico’s borders died from one disease.

Even allowing for those uncertainties, the scale is staggering. For comparison, the Black Death of the fourteenth century is often estimated to have killed roughly one-third to one-half of Europe’s population, although mortality differed considerably between regions. The cocoliztli epidemic belongs in any serious discussion of the greatest demographic catastrophes in human history.

And unlike some historical calamities that at least had the decency to occur once and then disappear, this one had an exceptionally unpleasant sequel.

By 1600, one influential historical reconstruction places the population of Mexico at approximately two million, compared with estimates of fifteen million to thirty million at the time of Spanish arrival. That decline cannot be attributed exclusively to cocoliztli. Smallpox, measles, other epidemics, warfare, hunger, displacement, and colonial exploitation all contributed to the collapse.

But even if the estimates remain debatable, the human consequences do not. Whole communities lost the people responsible for growing food, raising children, transmitting cultural knowledge, and maintaining the institutions upon which ordinary life depended. When a population loses such a large proportion of its members, the damage cannot be measured simply by counting graves.

The People Who Recorded the Horror

Fortunately for historians, and unfortunately for the people who had to experience it, the epidemic did not pass entirely without documentation. Both Indigenous observers and Spanish chroniclers recorded the disaster, leaving accounts that reveal what happened when death became an ordinary feature of daily life.

A particularly haunting record appears in the Tira de Tepechpan, a pictorial history created by an Indigenous painter-historian in the community of Tepechpan, north of Mexico City. Its depiction of the year 1545 includes a dead figure with blood emerging from the nose and mouth. Another figure represents the death of a local ruler. The terrible event was important enough to be permanently recorded in the community’s history.

Other Indigenous manuscripts also preserve images of the epidemic. These are more than illustrations accompanying somebody else’s account. They are historical testimony from people whose communities experienced the catastrophe firsthand, and they help us understand the disaster beyond the reports produced by colonial officials. The surviving pictorial record of Tepechpan is an especially powerful reminder that the victims were not simply statistics in a European history.

There were also written reports of entire communities becoming overwhelmed. As deaths mounted, the surviving residents could no longer care for everyone who was ill. Burial customs were disrupted, communal institutions struggled to function, and families were left trying to preserve some semblance of ordinary life while people around them continued to die.

Imagine a community in which several people die every day. Then imagine that the number rises to twenty, thirty, or forty. The people who ordinarily prepared the dead for burial are themselves sick. Those who would help care for orphans are mourning their own children. Even the simple act of digging graves becomes a problem when there are too few healthy people left to perform the work.

That’s the reality obscured by a figure like fifteen million. An epidemic doesn’t kill millions of people all at once in one convenient historical event. It destroys families and communities one death at a time, until the cumulative loss becomes almost impossible to comprehend.

1576: When the Disease Came Back

In 1576, approximately three decades after the first great outbreak, another devastating epidemic swept across Mexico. By then, Indigenous communities were still struggling with the consequences of the earlier catastrophe. Whatever recovery had occurred was about to receive a very unwelcome interruption.

The second epidemic moved rapidly through central Mexico and eventually reached communities across a much wider region. Historical analyses suggest that this outbreak killed an additional two million to two and a half million people, representing an enormous proportion of the surviving Indigenous population.

One of the most important medical witnesses was Francisco Hernández, a Spanish physician who had served King Philip II and was appointed to investigate the natural history of New Spain. Hernández encountered the epidemic personally and recorded its symptoms with a precision that continues to interest medical historians.

He described burning fevers, blackened tongues, extraordinary thirst, jaundice, weakness, delirium, convulsions, and severe bleeding. His observations were detailed enough that researchers have spent centuries attempting to match them with a recognizable disease.

Hernández had the considerable advantage of seeing the patients firsthand. Unfortunately, he had the equally considerable disadvantage of practicing medicine before the discovery of bacteria, viruses, antibiotics, modern epidemiology, or the germ theory of disease. He could describe what was happening with admirable accuracy while remaining unable to explain why it was happening.

The Franciscan chronicler Juan de Torquemada also described the enormous social consequences of the epidemic, including the overwhelming number of deaths and the difficulties of burying victims. His testimony provides an important picture of what happened beyond the sickbed, as communities struggled with losses that normal institutions could no longer manage.

Later researchers examining historical accounts and population records from the 1576 epidemic found that the outbreak spread rapidly and affected Indigenous populations particularly severely. Yet those records also exposed a puzzle: why did the disease devastate some populations while leaving others comparatively untouched?

It was a question that would eventually lead investigators away from the written records and into an unexpected place: the climate history of sixteenth-century Mexico.

Did Drought Help Turn an Epidemic Into a Catastrophe?

One of the more intriguing theories concerning cocoliztli has nothing to do with physicians or medical records. It begins with trees, which have the useful habit of recording environmental conditions without asking anyone to write down the weather.

By examining tree rings, researchers can reconstruct patterns of rainfall and drought extending back hundreds of years. Trees generally grow differently during wet years than during dry ones, leaving evidence of past climatic conditions within their wood. They are essentially exceptionally patient meteorologists, although their forecasts tend to arrive several centuries late.

Studies of tree rings revealed that sixteenth-century Mexico experienced an extraordinary period of drought. The years surrounding the great cocoliztli epidemics included severe environmental stress, with evidence suggesting that unusually dry conditions and later periods of heavier rainfall may have influenced the outbreaks.

One proposed explanation involves rodents. Under this hypothesis, environmental changes could have affected rodent populations or their interactions with humans, helping spread an unidentified infectious agent. Scientists exploring this possibility suggested that a native hemorrhagic fever might have been responsible for at least some of the historical epidemics.

The possibility is intriguing, particularly because it would mean that a disaster initially understood as a mysterious disease was also connected to a much larger environmental crisis. Researchers exploring the relationship between megadrought and mass mortality in sixteenth-century Mexico emphasized how climatic and social conditions may have magnified the effects of infection.

None of this establishes that rodents transmitted cocoliztli, or even that the disease was viral. Those remain hypotheses, and later genetic discoveries have introduced other possibilities. The evidence does, however, suggest that the circumstances in which an epidemic occurs can be just as consequential as the organism responsible for it.

Drought causes crops to fail. Food shortages weaken people’s ability to endure illness. Overcrowding, poor sanitation, and displacement can increase exposure to infectious diseases. In colonial Mexico, these problems were compounded by forced labor and exploitation that left many Indigenous people particularly vulnerable.

The climate theory also provides an interesting parallel to our earlier investigation into whether gerbils, rather than rats, helped spread outbreaks of the Black Death. In both cases, researchers have explored whether environmental changes altered the behavior and distribution of animals carrying dangerous pathogens.

Unfortunately, knowing that climate may have helped create favorable conditions for an epidemic still leaves one rather important question unanswered.

What, exactly, was the disease?

The 500-Year-Old Clue Hidden in Human Teeth

For centuries, investigators trying to identify cocoliztli relied upon historical descriptions, demographic records, geography, and educated speculation. Then modern genetics offered a new possibility: rather than trying to determine what people had died from by reading descriptions of their symptoms, perhaps scientists could search directly for evidence of the organisms that infected them.

This brings us to Teposcolula-Yucundaa, an archaeological site in Oaxaca, Mexico, where researchers investigated a cemetery associated with the sixteenth-century epidemic. The individuals buried there had died centuries before the invention of a microscope, much less the development of sophisticated DNA sequencing technology. Nevertheless, their remains preserved information that no written account could provide.

In 2018, an international research team published a remarkable discovery in Nature Ecology & Evolution. By analyzing ancient DNA recovered from the remains of people buried in the cemetery, the researchers identified genetic evidence of a bacterium called Salmonella enterica, specifically the serovar Paratyphi C, in ten individuals.

Now, when most people hear the word Salmonella, they think of undercooked chicken, contaminated eggs, and spending an exceptionally unpleasant weekend becoming better acquainted with their bathroom. That’s understandable, but it doesn’t fully describe the threat posed by this particular type of bacterium.

Paratyphi C can cause enteric fever, a serious systemic infection related to typhoid fever. Instead of producing only the familiar symptoms of food poisoning, the bacteria can enter the bloodstream and cause a potentially life-threatening illness. In an era without antibiotics, safe drinking water systems, or an understanding of bacterial transmission, such an infection could be especially dangerous.

What made the discovery particularly compelling was that the remains came from a cemetery associated with the 1545 epidemic. The 2018 genetic investigation of the Teposcolula-Yucundaa victims provided direct molecular evidence that this bacterium had infected people during the period of the catastrophe.

And how did scientists obtain that evidence? From the teeth of people who had been buried nearly five centuries earlier.

Teeth can offer a protected environment for preserving biological material over long periods. During a bloodstream infection, traces of a pathogen may reach tissues within the tooth. Under favorable conditions, fragments of bacterial DNA can survive long after the person has died. Modern laboratory methods can then identify these fragments and compare them with known microbial genomes.

The technology is extraordinary. Scientists can examine tiny fragments of ancient genetic material, distinguish possible pathogens from other microorganisms, and reconstruct parts of an organism’s genetic history. It’s rather like conducting a criminal investigation in which the evidence has spent five centuries underground and the laboratory has to reconstruct the suspect from scraps of a genetic calling card.

But there is an important limitation. Finding Paratyphi C in several victims does not prove that it caused every death at Teposcolula-Yucundaa, much less every outbreak called cocoliztli across Mexico. The bacterium may have been a major cause of the local epidemic, one contributor among several, or part of a larger pattern of infectious disease.

There is also the problem that some of the historical symptoms, especially the dramatic hemorrhaging described in later accounts, do not fit neatly into the typical modern description of paratyphoid fever. That discrepancy has kept the debate alive.

The researchers had identified a promising suspect, but the investigation was far from over. History, like a particularly uncooperative witness, was still withholding important information.

Did the Epidemic Leave a Mark on Human DNA?

As remarkable as the discovery of bacterial DNA in centuries-old teeth was, another genetic investigation produced an equally intriguing possibility. What if the great epidemics not only killed millions of people but also influenced the genetic characteristics of the generations that survived?

In 2024, researchers published a study examining ancient human DNA from Chichén Itzá, the famous Maya archaeological site in Mexico’s Yucatán Peninsula. The investigation involved genetic information obtained from the remains of 64 children who had lived centuries before European contact, along with genetic data from present-day Maya people living in the region.

The ancient remains came from a ritual burial context, not from victims of cocoliztli. Their importance to the epidemic investigation was something quite different: they provided a glimpse of the genetic characteristics of people who lived before the catastrophic diseases of the colonial period.

When researchers compared the ancient and modern populations, they identified changes involving genes associated with the human immune system. Some of those differences involved genetic variants that may provide greater protection against infections caused by Salmonella.

Here’s why that’s significant. When a population experiences a devastating epidemic, individuals with genetic characteristics that offer some protection against the disease may be more likely to survive and have descendants. Over many generations, those protective variants can become more common in the population. This is one of the mechanisms of natural selection.

In this case, the researchers found patterns consistent with the possibility that severe infectious diseases during the colonial era influenced the genetic makeup of surviving Maya populations. Their 2024 study of ancient Maya genomes identified immune-related changes potentially connected to exposure to enteric fever and other introduced diseases.

The finding is remarkable because it suggests that the consequences of sixteenth-century epidemics may extend beyond written histories, archaeological remains, and population statistics. Some of the effects may be reflected in the biological inheritance of people living today.

That does not mean scientists have identified a specific genetic signature proving that cocoliztli caused these changes. Several epidemic diseases affected the region, and other historical population changes could also have influenced genetic variation. The evidence supports an intriguing hypothesis rather than a definitive diagnosis of a five-century-old catastrophe.

Still, consider the extraordinary span of time involved. An epidemic devastates Indigenous populations during the sixteenth century. Centuries later, researchers examine the DNA of people who lived before the disaster and compare it with that of their modern descendants. The comparison may reveal evidence that infectious diseases helped shape which genetic characteristics became more common.

Most people leave history behind in the form of documents, buildings, possessions, or occasionally an embarrassing family story that refuses to die. The great epidemics of colonial Mexico may have left something considerably more enduring.

Why the Cocoliztli Mystery Remains Unsolved

So, after nearly five centuries of investigation, have we finally identified the disease responsible for one of history’s deadliest epidemics?

Not quite. The discovery of Salmonella Paratyphi C in victims buried during the 1545 epidemic represents a major scientific breakthrough, but it does not settle every question. The historical accounts describe symptoms that could reflect more than one disease, the epidemics affected different regions over many years, and researchers have only examined a tiny fraction of the people who died.

One possibility is that enteric fever was a significant contributor to the 1545 catastrophe. Another is that different pathogens caused different outbreaks that historical observers grouped together under the broad label of cocoliztli. It is also possible that multiple infections circulated simultaneously, their effects intensified by malnutrition, drought, inadequate sanitation, and the harsh circumstances of colonial life.

The proposed hemorrhagic-fever explanation remains part of the historical debate, but no particular virus has been conclusively identified as the cause. The suggestion that the disease was spread by rodents is likewise unproven. Modern scientists have several plausible lines of inquiry, but the evidence does not yet justify declaring the mystery solved.

What is beyond dispute is the enormous suffering experienced by Indigenous communities in sixteenth-century Mexico. The epidemic was not simply an isolated medical event. It unfolded amid conquest, colonization, forced labor, displacement, and repeated outbreaks of infectious disease. Those conditions profoundly shaped the disaster and its consequences.

For nearly 500 years, the victims of cocoliztli had little to offer historians beyond the testimony of those who witnessed their deaths. Physicians could describe the symptoms but could not identify the cause. Chroniclers recorded the devastation, while Indigenous historians preserved the catastrophe in words and images. Generations of researchers examined the surviving evidence without reaching a definitive answer.

Then scientists began examining the teeth of people buried during the epidemic, and the dead supplied evidence that their physicians never could.

The investigation is far from finished, but the progress is extraordinary. Five centuries after millions of people died from a mysterious illness, modern technology has allowed researchers to identify a possible bacterial culprit and explore whether the epidemics affected the genetic inheritance of surviving populations.

History has produced its share of unsolved mysteries, from vanished civilizations to unexplained disasters. The cocoliztli epidemic is unusual because researchers are still making discoveries about it using evidence that was buried long before anyone understood what DNA was.

It’s a remarkable achievement for an investigation in which the principal witnesses have been unavailable for questioning for nearly 500 years.

---