There is consensus among historians that smallpox struck central Mexico in 1520, the first of a series of devastating, multi-year epidemics that erupted in the sixteenth-century. A few months before January 1, 1521, when Hernán Cortes began his third trek to Tenochtitlan, now intent on subduing the Aztec capital by siege and sword, smallpox erupted in the heartland of the most powerful empire in Mesoamerica, killing the emperor Cuitlahuatzin, many caciques and warriors, and many women and children. The epidemic was particularly severe because, unlike in Europe, where the virus was a childhood disease, in Mexico it found "virgin soil," striking entire households, adults as well as children, in one massive blow. With almost everyone ill at once, there was no one to provide food, water, or care so that many who fell ill died, not of smallpox, but of hunger, dehydration, and despair.
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Measles hit for the first time in 1531. When smallpox returned in 1532 and 1538, mortality was lessened because many adults, now immune from having survived an earlier attack, were available to provide care to those who fell ill. A second great multi-year epidemic struck in 1545 (cocoliztli, typhus?, hemorrhagic fever?—the identification of sixteenth-century epidemics is almost as contentious as the dispute over the number of natives at contact) and a third in 1576 (matlazahuatl, perhaps typhus carried by human lice). Although a lively debate continues over which was most severe (the German scholar Hans Prem favors the first, that of 1520-21), it is clear that the effects of each were catastrophic.
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Recovery of the native population began, nonetheless, by the middle of the seventeenth-century according to most accounts. Rosenblat places the nadir at 3.4 million Indians around 1650, but, as noted above, Aguirre-Beltrán reckons the figure at only 1.3 million (plus 400,000 non-Indians). It is surprising that the Argentine linguist’s figures are more than double those of the Mexican anthropologist-historian even though both cite the same source, Juan Diez de la Calle.
Recovery was accompanied by a great mixing of peoples of different ethno-racial backgrounds. The only comprehensive figures on the subject for the entire colonial period were crafted by Aguirre-Beltrán. Figure 2 roughs out the evolution of the three principal ethnic stocks—Indian, African and European—and their intermixtures from conquest to the last decade of colonial rule. Indians always made up the overwhelming majority of the population of colonial Mexico, and people of solely African or European origin were always only minor fractions. The second largest group by the end of the sixteenth-century was the "Euromestizos," that is, Spanish-speakers of mixed Indian and European stock. Within a century of conquest Indo-mestizos (mixed stock Indian speakers) and Afro-mestizos (Spanish-speaking mixed groups with an African component) also made up a sizeable fraction of the population.