© The Author(s) 2018. Background: Cancer survivors are at increased risk of sepsis, possibly attributed to weakened physiologic conditions. The aims of this study were to examine the mediation effect of indicators of frailty on the association between cancer survivorship and sepsis incidence and whether these differences varied by race. Methods: We performed a prospective analysis using data from the REasons for Geographic and Racial Differences in Stroke cohort from years 2003 to 2012. We categorized frailty as the presence of ≥2 frailty components (weakness, exhaustion, and low physical activity). We categorized participants as “cancer survivors” or “no cancer history” derived from self-reported responses of being diagnosed with any cancer. We examined the mediation effect of frailty on the association between cancer survivorship and sepsis incidence using Cox regression. We repeated analysis stratified by race. Results: Among 28 062 eligible participants, 2773 (9.88%) were cancer survivors and 25 289 (90.03%) were no cancer history participants. Among a total 1315 sepsis cases, cancer survivors were more likely to develop sepsis (12.66% vs 3.81%, P <.01) when compared to participants with no cancer history (hazard ratios: 2.62, 95% confidence interval: 2.31-2.98, P <.01). The mediation effects of frailty on the log-hazard scale were very small: weakness (0.57%), exhaustion (0.31%), low physical activity (0.20%), frailty (0.75%), and total number of frailty indicators (0.69%). Similar results were observed when stratified by race. Conclusion: Cancer survivors had more than a 2-fold increased risk of sepsis, and indicators of frailty contributed to less than 1% of this disparity.