OBJECTIVES: In the United States, sepsis is a major public health problem accounting for over 200,000 annual deaths. The aims of this study were to identify U.S. counties with high sepsis mortality and to assess the community characteristics associated with increased sepsis mortality. DESIGN: We performed a descriptive analysis of 2003 through 2012 Compressed Mortality File data. We defined sepsis deaths as deaths associated with an infection, classified according to the International Classification of Diseases, 10th Version. SETTING: Three thousand one hundred and eight counties in the contiguous U.S. counties, excluding Hawaii and Alaska. MEASUREMENTS AND MAIN RESULTS: Using geospatial autocorrelation methods, we defined county-level sepsis mortality as strongly clustered, moderately clustered, and nonclustered. We approximated the mean crude, age-adjusted, and community-adjusted sepsis mortality rates nationally and for clustering groups. We contrasted demographic and community characteristics between clustering groups. We performed logistic regression for the association between strongly clustered counties and community characteristics. Among 3,108 U.S. counties, the age-adjusted sepsis mortality rate was 59.6 deaths per 100,000 persons (95% CI, 58.9-60.4). Sepsis mortality was higher in the Southern U.S. and clustered in three major regions: Mississippi Valley, Middle Georgia, and Central Appalachia. Among 161 (5.2%) strongly clustered counties, age-adjusted sepsis mortality was 93.1 deaths per 100,000 persons (95% CI, 90.5-95.7). Strongly clustered sepsis counties were more likely to be located in the south (92.6%; p < 0.001), exhibit lower education, higher impoverished population, without medical insurance, higher medically uninsured rates, and had higher unemployment rates (p < 0.001). CONCLUSIONS: Sepsis mortality is higher in the Southern United States, with three regional clusters: "Mississippi Valley," "Middle Georgia," and "Central Appalachia": Regions of high sepsis mortality are characterized by lower education, income, employment, and insurance coverage.