© 2016 S. Karger AG, Basel. Background: Is the high stroke mortality in the Southeastern parts of the United States driven by differences in stroke incidence or case-fatality? This question remains unanswered. Differences in incidence would underscore the need for stroke prevention, while differences in case fatality would call for improved stroke care. Methods: Quartiles of US counties were defined by stroke mortality, and this gradient was related with stroke incidence and stroke case fatality in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study, where 1,317 incident stroke events (of which 242 were fatal) occurred among 29,650 participants. Results: There was a significant (p = 0.0025) gradient of fatal stroke events in REGARDS (quartile 4 vs. quartile 1 (Q4/Q1) hazard ratio 1.95, 95% CI 1.35-2.81), demonstrating the consistency of REGARDS with national mortality data. The gradient for incident stroke (fatal + nonfatal) was also significant (p = 0.0023; Q4/Q1 hazard ratio 1.29, 95% CI 1.10-1.52). The gradient for stroke case-fatality was marginally significant (p = 0.058), though the OR for Q4/Q1 (1.71, 95% CI 1.13-2.25) was large. Conclusions: Both stroke incidence and case-fatality in REGARDS appear to be contributing, underscoring the need for strengthening both stroke prevention and acute stroke care in order to reduce the disparity.