© The Author 2017; Published by Oxford University Press on behalf of the International Epidemiological Association. All rights reserved. Background: Sepsis may contribute to more than 200 000 annual deaths in the USA. Little is known about the regional patterns of sepsis mortality and the community characteristics that explain this relationship. We aimed to determine the influence of community characteristics upon regional variations in sepsis incidence and case fatality. Methods: We performed a retrospective analysis of data from the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Using US sepsis mortality data, we used two strategies for defining geographic regions: (i) Sepsis 'Belt' vs Non-Belt and (ii) Sepsis 'Cluster' vs Non-Cluster. We determined sepsis incidence and case fatality among REGARDS participants in each region, adjusting for participant characteristics. We examined the mediating effect of community characteristics upon regional variations in sepsis incidence and case fatality. Results: Among 29 680 participants, 16 493 (55.6%) resided in the Sepsis Belt and 2958 (10.0%) resided in a Sepsis Cluster. Sepsis incidence was higher for Sepsis Belt than Non-Belt participants [adjusted hazard ratio (HR)=1.14; 95% confidence interval (CI)=1.02-1.24] and higher for Sepsis Cluster than Non-Cluster participants (adjusted HR=1.18; 95% CI=1.01-1.39). Sepsis case fatality was similar between Sepsis Belt and Non-Belt participants, as well as between Cluster and Non-Cluster participants. Community poverty mediated the regional differences in sepsis incidence. Conclusions: Regional variations in sepsis incidence may be partly explained by community poverty. Other community characteristics do not explain regional variations in sepsis incidence or case fatality.