Background and Purpose - Stroke mortality is 30% higher in the rural United States. This could be because of either higher incidence or higher case fatality from stroke in rural areas. Methods - The urban-rural status of 23 280 stroke-free participants recruited between 2003 and 2007 in the REGARDS study (Reasons for Geographic and Racial Differences in Stroke) was classified using the Rural-Urban Commuting Area scheme as residing in urban, large rural town/city, or small rural town or isolated areas. The risk of incident stroke was assessed using proportional hazards analysis, and case fatality (death within 30 days of stroke) was assessed using logistic regression. Models were adjusted for demographics, traditional stroke risk factors, and measures of socioeconomic status. Results - After adjustment for demographic factors and relative to urban areas, stroke incidence was 1.23-times higher (95% confidence intervals, 1.01-1.51) in large rural town/cities and 1.30-times higher (95% confidence intervals, 1.03-1.62) in small rural towns or isolated areas. Adjustment for risk factors and socioeconomic status only modestly attenuated this association, and the association became marginally nonsignificant (P=0.071). There was no association of rural-urban status with case fatality (P>0.47). Conclusions - The higher stroke mortality in rural regions seemed to be attributable to higher stroke incidence rather than case fatality. A higher prevalence of risk factors and lower socioeconomic status only modestly contributed to the increased risk of incident stroke risk in rural areas. There was no evidence of higher case fatality in rural areas.