OBJECTIVE: Sepsis, the syndrome of microbial infection complicated by systemic inflammation, is associated with significant morbidity and mortality. To determine if obesity increases risk of sepsis events. DESIGN AND METHODS: Data from the 30,239 subject population-based longitudinal cohort study REasons for Geographic and Racial Differences in Stroke (REGARDS) were used. Using measurements at the start of the study, we defined obesity using body mass index (BMI; <18.5 kg/m(2) = underweight, 18.5-24.9 = normal, 25.0-29.9 = overweight, 30.0-39.9 = obese, ≥40 = morbidly obese) and waist circumference (WC; [male ≤102 cm or female ≤88 cm] = normal, [male >102 cm or female >88 cm] = obese). Over an 8-year observation period, we evaluated the association between obesity and subsequent sepsis events, adjusting for sociodemographic factors, health behaviors, chronic medical conditions, statin use, and high-sensitivity C-reactive protein. RESULTS: There were 975 incident sepsis events. Compared to those with a BMI of 18.5-24.9, sepsis risk was higher only for BMI ≥ 40 (hazard ratio [HR] 1.57, [1.16-2.14]). Risk of sepsis was associated with increased WC (HR 1.34 [1.14-1.56]). In a model with both BMI and WC, sepsis risk was associated with increased WC (HR 1.47 [1.20-1.79]) but not BMI. CONCLUSIONS: Obesity is independently associated with future sepsis events. WC is a better predictor of future sepsis risk than BMI.