After first contacts with Europeans and Africans, some believe that the death of 90â95% of the native population of the New World was caused by Old World diseases.[62] It is suspected that smallpox was the chief culprit and responsible for killing nearly all of the native inhabitants of the Americas. For more than 200 years, this disease affected all new world populations, mostly without intentional European transmission, from contact in the early 1500s to until possibly as late as the French and Indian Wars (1754–1767).[63]

In 1519 Hernán Cortés landed on the shores of what is now Mexico and was then the Aztec empire. In 1520 another group of Spanish arrived in Mexico from Hispaniola, bringing with them the smallpox which had already been ravaging that island for two years. When Cortés heard about the other group, he went and defeated them. In this contact, one of Cortés's men contracted the disease. When Cortés returned to Tenochtitlan, he brought the disease with him.

Soon, the Aztecs rose up in rebellion against Cortés and his men. Outnumbered, the Spanish were forced to flee. In the fighting, the Spanish soldier carrying smallpox died. After the battle, the Aztecs contracted the virus from the invaders' bodies.[citation needed] Cortes would not return to the capital until August 1521. In the meantime smallpox devastated the Aztec population. It killed most of the Aztec army and 25% of the overall population.[64] A Spanish priest left this description: "As the Indians did not know the remedy of the disease…they died in heaps, like bedbugs. In many places it happened that everyone in a house died and, as it was impossible to bury the great number of dead, they pulled down the houses over them so that their homes become their tombs."[citation needed] On Cortés's return, he found the Aztec army’s chain of command in ruins. The soldiers who lived were still weak from the disease. Cortés then easily defeated the Aztecs and entered Tenochtitlán.[65] The Spaniards said that they could not walk through the streets without stepping on the bodies of smallpox victims.[citation needed]

The effects of smallpox on Tahuantinsuyu (or the Inca empire) were even more devastating. Beginning in Colombia, smallpox spread rapidly before the Spanish invaders first arrived in the empire. The spread was probably aided by the efficient Inca road system. Within months, the disease had killed the Sapa Inca Huayna Capac, his successor, and most of the other leaders. Two of his surviving sons warred for power and, after a bloody and costly war, Atahualpa become the new Sapa Inca. As Atahualpa was returning to the capital Cuzco, Francisco Pizarro arrived and through a series of deceits captured the young leader and his best general. Within a few years smallpox claimed between 60% and 90% of the Inca population,[66] with other waves of European disease weakening them further. A handful of historians argue that a disease called Bartonellosis may have been responsible for some outbreaks of illness, but this opinion is in the scholarly minority.[67] The effects of smallpox were depicted in the ceramics of the Moche people of ancient Peru.[68]

Even after the two mighty empires of the Americas were defeated by the virus and disease, smallpox continued its march of death. In 1633 in Plymouth, Massachusetts, the Native Americans were struck by the virus. As it had done elsewhere, the virus wiped out entire population groups of Native Americans. It reached Mohawks in 1634,[69] the Lake Ontario in 1636, and the lands of the Iroquois by 1679. During the 1770s, smallpox killed at least 30% of the West Coast Native Americans.[70][71] Smallpox epidemic of 1780–1782 brought devastation and drastic depopulation among the Plains Indians.[72] By 1832, the federal government of the United States established a smallpox vaccination program for Native Americans.[73]

A particularly virulent sequence of smallpox outbreaks took place in Boston, Massachusetts. From 1636 to 1698, Boston endured six epidemics. In 1721, the most severe epidemic occurred. The entire population fled the city, bringing the virus to the rest of the Thirteen Colonies. In the late 1770s, during the American Revolutionary War, smallpox returned once more and killed an estimated 125,000 people.[74] Peter Kalm in his Travels in North America, described how in that period, the dying Indian villages became overrun with wolves feasting on the corpses and weakened survivors.[75]