Not all of these deaths were caused by disease, of course; forced labor, starvation, cruelty, murder, rape, enslavement, and relocation also contributed mightily to the extinction of the Taíno Indians of Hispaniola and the other peoples of the Caribbean. But the overriding factor was European disease, against which the New World had almost no resistance. Modern epidemiologists have studied the old accounts to figure out what diseases struck down the Indians during these first epidemics. Their best guesses are influenza, typhus, and dysentery. Many later diseases joined the first in triggering wave after wave of mortality, including measles, mumps, yellow fever, malaria, chicken pox, typhoid, plague, diphtheria, whooping cough, tuberculosis, and—deadliest of all—smallpox.

These epidemics did not stay in the islands. Las Casas described a “drag-net” of death that spread to the Central American mainland “and devastated all this sphere.” Native traders may have first spread contagion to the mainland before 1500; people may have begun dying there even before Europeans arrived. But we know for certain that Columbus, on his fourth voyage in 1502, inadvertently unleashed disease on mainland America.

While probing for a passage westward to the Indies, Columbus reached Honduras’s Bay Islands on July 30, 1502. After spending a few weeks in the islands, he sailed on to the Central American main, becoming the first European to touch land there. He anchored in a harbor near the present-day town of Trujillo, and he christened the new land “Honduras” (the Depths) because of the very deep water he had encountered near shore. After disembarking on the Honduran mainland, he and his men held a Christian mass on August 14, 1502, and claimed the land for Isabella and Ferdinand of Spain.

After meeting with friendly Indians, Columbus, who was ill yet again (with what we are not sure), continued exploring southward with his many sick men, sailing along the coastline of Honduras, Nicaragua, and Panama, stopping frequently along the way. Like spot fires set in a forest, disease spread outward from these points of contact, burning deep into the interior lands, far outracing actual European exploration. We do not know how many died in these first epidemics; the natives who witnessed them did not leave any accounts, and there were no European chroniclers.

But the real apocalypse was yet to come. That arrived in the form of smallpox. Las Casas wrote that “it was carried by someone from Castile,” and it arrived in Hispaniola in December of 1518. “Of the immensity of peoples that this island held, and that we have seen with our own eyes,” Las Casas wrote, only “a thousand” were left by the end of 1519. In January it spread to Puerto Rico, and from there it raged across the Caribbean and jumped to the mainland. By September of 1519, smallpox had reached the Valley of Mexico.

Traditional Indian remedies against illness—sweats, cold baths, and medicinal herbs—were ineffective against smallpox. Indeed, many efforts at healing only seemed to hasten death. In Europe, at its worst, smallpox killed about one out of three people it infected; in the Americas the death rate was higher than 50 percent and in many cases approached 90 to 95 percent.

Epidemiologists generally agree that smallpox is the cruelest disease ever to afflict the human race. In the century before it was eradicated in the 1970s, it killed more than half a billion people and left millions of others horribly scarred and blind. It inflicts unbearable suffering, both physical and psychological. It usually starts like the flu, with headache, fever, and body aches; and then it breaks out as a sore throat that soon spreads into a body rash. As the disease develops over the subsequent week, the victim often experiences frightful hallucinatory dreams and is racked by a mysterious sensation of existential horror. The rash turns into spots that swell into papules, and then fluid-filled pustules that cover the entire body, including the soles of the feet. These pustules sometimes merge, and the outer layer of skin becomes detached from the body. In the most deadly variety of smallpox, the hemorrhagic form, called the bloody pox or black pox, the skin turns a deep purple or takes on a charred look, and comes off in sheets. The victim often “bleeds out,” blood pouring from every orifice in the body. It is extremely contagious. Unlike most other viruses, smallpox can survive and remain virulent for months or years outside the body in clothing, blankets, and sickrooms.

The Indians were in abject terror of it. It was like nothing they had ever experienced before. The history of the Conquest contains many Spanish eyewitness accounts attesting to the horrors of the pandemic. “It was a dreadful illness,” wrote one friar, “and many people died of it. No one could walk; they could only lie stretched out on their beds. No one could move, not even able to turn their heads. One could not lie face down, or lie on the back, nor turn from one side to another. When they did move, they screamed in pain… Many died from it, but many died only of hunger. There were deaths from starvation, for they had no one left to care for them.”

These epidemics of disease weakened Indian military resistance, and in many instances it aided the Spanish in their conquest. But overall, the Spanish (and Columbus personally) were deeply dismayed by the vast die-offs; the deaths of so many Indians interfered with their slaving businesses, killed their servants, and emptied their plantations and mines of forced labor. When smallpox arrived, the Indians often responded with panic and flight, abandoning towns and cities, leaving behind the sick and dead. And while the Spanish were less susceptible to these epidemics, they were not immune, and many also died in the general conflagration.