Background and Purpose: The rate of cerebrovascular events within the stroke belt, a geographic area defined in the Southeastern United States, exceeds that of the rest of the nation. Despite evaluation of multiple risk factors for this disparity, specific causes for the stroke belt have not been elucidated. More than 45 years ago, the US Public Health Service and US Navy cooperative skin-testing program (1958-1965) documented adolescent exposure to Histoplasma capsulatum. Our purpose was to evaluate the association between exposure to Histoplasma capsulatum and subsequent development of stroke. Methods: A cross-sectional study of stroke in a cohort of US Navy veterans was designed to assess our hypothesis. Medical records from 23,795 men who participated in the cooperative skin-testing program and who received medical care at Veterans Administration Hospitals and Clinics were reviewed. A logistic regression model was used to estimate the odds ratio of stroke while controlling for multiple covariates. Because of the large number of possible risk factors for stroke, propensity scores were used to reduce bias. Results: The adjusted odds ratio for stroke in veterans exposed to Histoplasma capsulatum during adolescence was 1.34 (95% confidence interval: 1.1-1.6; P = .0033). The increased risk was independent of traditional cerebrovascular event risk factors. Less frequent risk factors (atrial fibrillation, coronary heart disease, rheumatic heart disease, and prosthetic cardiac valvular replacement) were not controlled in this model. Conclusion: Exposure to Histoplasma capsulatum during adolescence was associated with an increased risk of stroke. © 2008 National Stroke Association.