© 2018 The Authors Background: Hospitalized cancer patients are nearly 10 times more likely to develop sepsis when compared to patients with no cancer history. We compared the risk of sepsis between cancer survivors and no cancer history participants, and examined whether race was an effect modifier. Methods: We performed a prospective analysis of data from the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. We categorized participants as “cancer survivors” or “no cancer history” derived from self-reported responses of being diagnosed with any cancer, excluding non-melanoma skin cancer. We defined sepsis as hospitalization for a serious infection with ≥2 systemic inflammatory response syndrome criteria. We performed Cox proportional hazard models to examine the risk of sepsis after cancer (adjusted for sociodemographics, health behaviors, and comorbidities), and stratified by race. Results: Among 29,693 eligible participants, 2959 (9.97%) were cancer survivors, and 26,734 (90.03%) were no cancer history participants. Among 1393 sepsis events, the risk of sepsis was higher for cancer survivors (adjusted HR: 2.61, 95% CI: 2.29–2.98) when compared to no cancer history participants. Risk of sepsis after cancer survivorship was similar for Black and White participants (p value for race and cancer interaction = 0.63). Conclusion: In this prospective cohort of community-dwelling adults we observed that cancer survivors had more than a 2.5-fold increased risk of sepsis. Public health efforts should attempt to mitigate sepsis risk by awareness and appropriate treatment (e.g., antibiotic administration) to cancer survivors with suspected infection regardless of the number of years since cancer remission.