While overhunting and climate change have been the major hypotheses to explain the late-Pleistocene New World megafaunal extinctions, the role of introduced disease has only received brief attention. Here, we review pre-Columbian diseases endemic to aboriginal Americans and evaluate their potential to cause large-scale mortality in Pleistocene mammals. Of the probable communicable diseases present in pre-Columbian times, we regard anthrax and tuberculosis as viable candidates. These two diseases demonstrate characteristics that could have made them deadly to immunologically naïve populations. Introduced disease, as a primary cause or interacting with overhunting and climate change, could have contributed to the decline and extirpation of Pleistocene megafauna.