The early stages of the COVID-19 pandemic revealed stark regional variation in the spread of the virus. While previous research has highlighted the impact of regional differences in sociodemographic and economic factors, we argue that regional differences in social and compliance behaviors-the very behaviors through which the virus is transmitted-are critical drivers of the spread of COVID-19, particularly in the early stages of the pandemic. Combining self-reported personality data that capture individual differences in these behaviors (3.5 million people) with COVID-19 prevalence and mortality rates as well as behavioral mobility observations (29 million people) in the United States and Germany, we show that regional personality differences can help explain the early transmission of COVID-19; this is true even after controlling for a wide array of important sociodemographic, economic, and pandemic-related factors. We use specification curve analyses to test the effects of regional personality in a robust and unbiased way. The results indicate that in the early stages of COVID-19, Openness to experience acted as a risk factor, while Neuroticism acted as a protective factor. The findings also highlight the complexity of the pandemic by showing that the effects of regional personality can differ (a) across countries (Extraversion), (b) over time (Openness), and (c) from those previously observed at the individual level (Agreeableness and Conscientiousness). Taken together, our findings support the importance of regional personality differences in the early spread of COVID-19, but they also caution against oversimplified answers to phenomena as complex as a global pandemic.