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Residence in the Southeastern United States (US) has been linked to increased stroke incidence and mortality. However, data on regional variability in overall cardiovascular disease (CVD) and specific coronary heart disease incidence are sparse.We assessed the risk of major CVD (nonfatal stroke, nonfatal myocardial infarction, or death from CVD) and specific CVD associated with region of residence (Northeast, Southeast, Midwest, and West) in 17 927 apparently healthy male participants of the Physicians' Health Study. Subjects were aged 40 to 84, most were white (93%), and had no previous CVD at baseline. We used residence in the Northeast as the reference group and proportional hazards models to adjust for potential confounding.We found no difference in risk of major CVD between regions of residence. Further, we found no consistent association between myocardial infarction and CVD death and region of residence. In contrast, we found a significantly increased risk of total stroke (HR, 1.22; 95% CI, 1.02 to 1.47) associated with residence in the Southeast compared with the Northeast. This relative risk was further increased for ischemic stroke (HR, 1.30; 95% CI, 1.06 to 1.58). We saw no difference in risk of any outcome when categorizing state of residence into tertiles based on mean winter temperature, mean summer temperature, or into 2 groups based on latitude.In this homogenous and well-characterized cohort of US male physicians, we found greater incidence of ischemic stroke, but not other vascular events among those living in the Southeastern US, compared with other regions.