BACKGROUND: Studies have shown that aspirin used for secondary prevention significantly reduces cardiovascular and stroke risk. The data for aspirin and primary prevention of cardiovascular disease, and in particular stroke, are less clear, especially among blacks. OBJECTIVE: To evaluate prophylactic aspirin use and incident stroke in a large cohort of black and white participants. METHODS: The Reasons for Geographic and Racial Differences in Stroke study is a national, population-based, longitudinal study of 30,239 African Americans and whites, older than 45 years. Participants with stroke at baseline were excluded, reducing the cohort to 27,219. Proportional hazard models were used to estimate the association of incident stroke with prophylactic aspirin use, adjusted for confounding factors. Separate analyses were performed for subjects who self-reported baseline aspirin use for primary prevention of vascular disease compared with those using aspirin use for other indications. RESULTS: In all, 10,177 participants taking prophylactic aspirin were followed for a mean of 4.6 years. Univariate analysis showed an increased stroke risk for prophylactic aspirin use (hazard ratio [HR]: 1.37; 95% confidence interval: 1.16-1.62), but the association was attenuated (HR: 1.06; 95% CI: .86-1.32) with multivariable adjustment, adjusting for demographic factors (age, race, sex, and region), socioeconomic factors (income and education), perceived general health, cardiovascular disease (CVD) risk factors (hypertension, diabetes, dyslipidemia, cigarette smoking, and alcohol use), and finally the Framingham Stroke Risk Score (in a separate model). No racial, sex, or regional differences in the association were demonstrated. CONCLUSIONS: In this observational study, prophylactic aspirin use was not associated with risk of first stroke, and there were no sex, race, or regional differences.