BACKGROUND: Sepsis is the syndrome of body-wide inflammation triggered by infection and is a major public health problem. Diet plays a vital role in immune health but its association with sepsis in humans is unclear. METHODS: We examined 21,404 participants with available dietary data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a national cohort of 30,239 black and white adults ≥45 years of age living in the US. The primary exposures of interest were five empirically derived diet patterns identified via factor analysis within REGARDS participants: "Convenience" (Chinese and Mexican foods, pasta, pizza, other mixed dishes), "Plant-based" (fruits, vegetables), "Southern" (added fats, fried foods, organ meats, sugar-sweetened beverages), "Sweets/Fats" (sugary foods) and "Alcohol/Salads" (alcohol, green-leafy vegetables, salad dressing). The main outcome of interest was investigator-adjudicated first hospitalized sepsis events. RESULTS: A total of 970 first sepsis events were observed over ~6 years of follow-up. In unadjusted analyses, greater adherence to Sweets/Fats and Southern patterns was associated with higher cumulative incidence of sepsis, whereas greater adherence to the Plant-based pattern was associated with lower incidence. After adjustment for sociodemographic, lifestyle and clinical factors, greater adherence to the Southern pattern remained associated with higher risk of sepsis (hazard ratio [HR] comparing the fourth to first quartile, HR 1.39, 95 % CI 1.11,1.73). Race modified the association of the Southern diet pattern with sepsis (P interaction = 0.01), with the Southern pattern being associated with modestly higher adjusted risk of sepsis in black as compared to white participants (HR comparing fourth vs. first quartile HR 1.42, 95 % CI 0.75,2.67 vs. 1.21, 95 % CI 0.93,1.57, respectively). CONCLUSION: A Southern pattern of eating was associated with higher risk of sepsis, particularly among black participants. Determining reasons for these findings may help to devise strategies to reduce sepsis risk.