The geography of the 16th century cocoliztli epidemics supports the notion that they may have been indigenous fevers carried by rodents or other hosts native to the highlands of Mexico. In 1545 the epidemic affected the northern and central high valleys of Mexico and ended in Chiapas and Guatemala (4). In both the 1545 and 1576 epidemics, the infections were largely absent from the warm, low-lying coastal plains on the Gulf of Mexico and Pacific coasts (4). This geography of dis- ease is not consistent with the introduction of an Old World virus to Mexico, which should have affected both coastal and highland populations. Tree-ring evidence, reconstructed rainfall over Durango, Mexico during the 16th century (6), adds support to the hypothesis that unusual climatic conditions may have inter- acted with host-population dynamics and the cocoliztli virus to aggravate the epidemics of 1545 and 1576. The tree-ring data indicate that both epidemics occurred during the 16th century megadrought, the most severe and sustained drought to impact north central Mexico in the past 600 years (Figure 2; [7]). The scenario for the climatic, ecologic, and sociologic mediation of the 16th-century cocoliztli epidemics is reminiscent of the rodent population dynamics involved in the outbreak of han- tavirus pulmonary syndrome caused by Sin Nombre Virus on the Colorado Plateau in 1993 (8,9). Cocoliztli was not pulmo- nary and may not have been a hantavirus but may have been spread by a rodent host. If true, then the prolonged drought before the 16th-century epidemics would have reduced the available water and food resources. The animal hosts would then tend to concentrate around the remnants of the resource base, where heightened aggressiveness would favor a spread of the viral agent among this residual rodent population. Fol- lowing improved climatic conditions, the rodents may have invaded both farm fields and homes, where people were infected through aspiration of excreta, thereby initiating the cocoliztli epidemic. The native people of Mexico may have been preferentially infected because they worked the agricul- tural fields and facilities that were presumably infested with infected rodents. Ten lesser epidemics of cocoliztli began in the years 1559, 1566, 1587, 1592, 1601, 1604, 1606, 1613, 1624, and 1642 HISTORICAL REVIEW (10). Nine of them began in years in which the tree-ring recon- structions of precipitation indicate winter-spring (November- March) and early summer (May-June) drought (8). But the worst epidemic of cocoliztli ever witnessed, 1545-1548, actu- ally began during a brief wet episode within the era of pro- longed drought (Figure 3). This pattern of drought followed by wetness associated with the 1545 epidemic is very similar to the dry-then-wet conditions associated with the hantavirus out- break in 1993 (Figure 3; [9]), when abundant rains after a long drought resulted in a tenfold increase in local deer mouse pop- ulations. Wet conditions during the year of epidemic outbreak in both 1545 and 1993 may have led to improved ecologic conditions and may also have resulted in a proliferation of rodents across the landscape and aggravated the cocoliztli epi- demic of 1545-1548. The disease described by Dr. Hernandez in 1576 is difficult to link to any specific etiologic agent or disease known today. Some aspects of cocoliztli epidemiology suggest that a native Figure 2. Winter-spring precipitation reconstructed from tree ring data, Durango, Mexico (normalized and smoothed to highlight decennial variability). The tree-ring estimates explain 56% of the variance in pre- cipitation for Durango and are consistent with independent precipitation data. This reconstruction is well correlated with the all-Mexico rainfall index (r = 0.76; p < 0.001) and with precipitation over north central Mexico, where the cocoliztli epidemics appear to have been most severe. Note the unprecedented 16th-century megadrought during both cocoliztli epidemics. Figure 3. The winter-spring precipitation totals estimated for each year in Durango, 1540–1548 (top), 1571–1579 (middle), compared with the Palmer drought index, southwestern USA 1988–1995 (bottom). A ten- fold increase in deer mice was witnessed in the southwestern USA dur- ing the 1993 outbreak, a year of abundant precipitation following a prolonged drought. The similar dry-wet pattern reconstructed for the 1545 epidemic of cocoliztli may have impacted the population dynam- ics of the suspected rodent host to aggravate the epidemic. Emerging Infectious Diseases • Vol. 8, No. 4, April 2002 361