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The influence of recent ethnohistorical factors on the microevolution of South American Indians has not been adequately evaluated by population geneticists. This makes difficult a reasonable interpretation of the present genetic structure of these groups. In this article the genetic diversity of 18 tribes of the Amazon and neighboring areas belonging to 3 linguistic groups (Tupi, Carib, and Ge) is analyzed in light of documentary sources about historical events, such as demographic changes, geographic movements, intertribal relationships, and marriage practices, that have taken place since the end of the eighteenth century. The high depopulation rate suffered by the Tupi groups (61.4% on average) is a probable factor conditioning the large intergroup genetic distances in this linguistic stock, for depopulation is a phenomenon associated with random genetic drift caused by a bottleneck effect. On the other hand, the relatively high similarity of the Ge and the Carib shows an association with two main factors: (1) reduced spatial dispersion of the Ge in the recent past, providing adequate conditions for within-stock gene flow, and (2) strong tradition of intergroup contacts among the Carib, frequently followed by genetic admixture and even fusion of groups, as verified for the Wayana and the Aparaf. The patterns of biologic variation of some Tupi tribes (Waiapi, Emerillon, Parakana, and Assurini) are better explained by historical and regional contingencies than by linguistic classification.