In response to the Ebola scare in 2014, many people evinced strong fear and xenophobia. The present study, informed by the pathogen-prevalence hypothesis, tested the influence of individualism and collectivism on xenophobic response to the threat of Ebola. A nationally representative sample of 1,000 Americans completed a survey, indicating their perceptions of their vulnerability to Ebola, ability to protect themselves from Ebola (protection efficacy), and xenophobic tendencies. Overall, the more vulnerable people felt, the more they exhibited xenophobic responses, but this relationship was moderated by individualism and collectivism. The increase in xenophobia associated with increased vulnerability was especially pronounced among people with high individualism scores and those with low collectivism scores. These relationships were mediated by protection efficacy. State-level collectivism had the same moderating effect on the association between perceived vulnerability and xenophobia that individual-level value orientation did. Collectivism—and the set of practices and rituals associated with collectivistic cultures—may serve as psychological protection against the threat of disease.