PURPOSE: Elevated biomarkers of inflammation and endothelial cell activation have been associated with severity of sepsis. We sought to determine the association between these baseline markers and subsequent episodes of sepsis. MATERIALS AND METHODS: We performed a nested case-control analysis using subjects from the REasons for Geographic and Racial Differences in Stroke cohort. We compared 162 sepsis cases (hospitalized for a serious infection with ≥2 systemic inflammatory response syndrome criteria) with 162 nonsepsis controls (hospitalized for a serious infection but not sepsis) matched by age, sex, and observation time epoch. Using conditional logistic regression, we evaluated the associations between sepsis and baseline levels of interleukin-6 (IL-6), tumor necrosis factor α, E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), adjusting for smoking status, hypertension, and chronic kidney disease. RESULTS: Compared with controls, individuals with higher baseline IL-6, E-selectin, and ICAM-1 were more likely to develop sepsis (P values for trend=.02, .02, .04). Baseline tumor necrosis factor α and ICAM-1 were not associated with future sepsis (P values for trend=.29, .33). CONCLUSIONS: Individuals with higher baseline IL-6, E-selectin, and ICAM-1 were more likely to develop future sepsis episodes. These biomarkers may play a role in the early identification, mitigation, or prevention of sepsis.