Previous research has documented cross-cultural differences in personality traits, but the origins of those differences remain unknown. The authors investigate the possibility that these cultural differences can be traced, in part, to regional differences in the prevalence in infectious diseases. Three specific hypotheses are deduced, predicting negative relationships between disease prevalence and (a) unrestricted sociosexuality, (b) extraversion, and (c) openness to experience. These hypotheses were tested empirically with methods that employed epidemiological atlases in conjunction with personality data collected from individuals in dozens of countries worldwide. Results were consistent with all three hypotheses: In regions that have historically suffered from high levels of infectious diseases, people report lower mean levels of sociosexuality, extraversion, and openness. Alternative explanations are addressed, and possible underlying mechanisms are discussed.