The current study utilizes the current COVID-19 pandemic to highlight the importance of accounting for the influence of external political and economic factors in personality public-health research. We investigated the extent to which systemic factors modify the relationship between personality and pandemic response. Results shed doubt on the cross-cultural generalizability of common big-five factor models. Individual differences only predicted government compliance in autocratic countries and in countries with income inequality. Personality was only predictive of mental health outcomes under conditions of state fragility and autocracy. Finally, there was little evidence that the big five traits were associated with preventive behaviors. Our ability to use individual differences to understand policy-relevant outcomes changes based on environmental factors and must be assessed on a trait-by-trait basis, thus supporting the inclusion of systemic political and economic factors in individual differences models.