The parasite stress hypothesis predicts that individuals living in regions with higher infectious disease rates will show lower openness, agreeableness, and extraversion, but higher conscientiousness. This article, using data from more than 250,000 U.S. Facebook users, reports tests of these predictions at the level of both U.S. states and individuals and evaluates criticisms of previous findings. State-level results for agreeableness and conscientiousness are consistent with previously reported cross-national findings, but others (a significant positive correlation with extraversion and no correlation with openness) are not. However, effects of parasite stress on conscientiousness and agreeableness are not found when analyses account for the data's hierarchical structure and include controls. We find that only openness is robustly related to parasite stress in these analyses, and we also find a significant interaction with age: Older, but not younger, inhabitants of areas of high parasite stress show lower openness. Interpretations of the findings are discussed.