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Introduction: One NIH goal is to investigate the US nationwide rural-urban health disparities; however, few studies provide data to help understand the 30% higher rural stroke mortality. It is unknown if the higher stroke mortality is attributable to a higher incidence of stroke, or to a higher case fatality, in rural regions. Further, the role of risk factors or SES status in higher incidence or case-fatality is unknown.Methods: REGARDS participants stroke-free at baseline (n = 25,090) were stratified by Rural-Urban Commuting Area strata: urban, large rural city/town, or small rural town or isolated region. Participants were followed for incident stroke, and case fatality was defined as death within 30-days of a stroke. Difference in incident stroke was assessed using proportional hazards analysis, and case-fatality by logistic regression, each considered after adjustment for demographic factors, further adjustment for risk factors, and further adjustment for SES.Results: Over an average follow-up of 8.2 years, 1,060 incident strokes occurred, of which 160 died within 30 days. Risk of incident stroke increased with rurality (p = 0.016), with a hazard 1.21-times (95% CI: 1.00 - 1.46) higher in large rural cities/towns, and 1.24-times (95% CI: 1.00 - 1.54) higher in small rural towns or isolated regions (see table). Adjustment for risk factors and SES attenuated the estimated risk by 50%, and the association became non-significant. There was no evidence of a higher case-fatality from stroke in rural regions (p > 0.46).Discussion: The higher stroke mortality in rural regions appears to be attributable to higher stroke incidence, and not to higher case-fatality. Higher stroke incidence in rural regions is partially attributable to a worse risk factor profile and lower SES. Efforts to reduce rural disparity in stroke mortality should focus on preventive strategies, especially those relevant to risk factor development and control, and/or mitigating the impact of lower SES.