For at least 50 years, stroke death rates have been higher in the southeast region of the United States than in other US regions. To test the hypotheses that stroke incidence is higher in the Southeast than in other regions and that higher levels of known stroke risk factors in the Southeast explain the difference in incidence, data were analyzed from a nationally representative, longitudinal cohort study of a sample drawn from the US population, the First National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Followup Study (1971-1987). In white men and women aged 45-74 years, the risk of stroke was significantly higher in the Southeast than the Northeast or the West in men and the Midwest in women. In white men, this excess risk could not be explained by regional differences in multiple stroke risk factors (Northeast vs. Southeast risk-adjusted relative risk = 0.71, 95% confidence interval 0.52-0.98). In white women, some of the excess risk associated with residence in the Southeast compared with the Midwest could be explained by the regional differences in risk factors measured in NHANES I (Midwest vs. Southeast risk-adjusted relative risk = 0.73, 95% confidence interval 0.53-1.00). In blacks, regional differences that were statistically significant could not be demonstrated. However, a strong association of increased stroke risk with nonmetropolitan residence in blacks was demonstrated that was independent of region or other stroke risk factors. Higher stroke incidence rates in the Southeast contribute to the higher stroke mortality rates in that US region.