Abstract Purpose Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. The purpose of the study was to measure the associations of specific exposures (deprivation, ethnicity, and clinical characteristics) with incident sepsis and case fatality. Methods Two research databases in England were used including anonymized patient-level records from primary care linked to hospital admission, death certificate, and small-area deprivation. Sepsis cases aged 65–100 years were matched to up to six controls. Predictors for sepsis (including 60 clinical conditions) were evaluated using logistic and random forest models; case fatality rates were analyzed using logistic models. Results 108,317 community-acquired sepsis cases were analyzed. Severe frailty was strongly associated with the risk of developing sepsis (crude odds ratio [OR] 14.93; 95% confidence interval [CI] 14.37–15.52). The quintile with most deprived patients showed an increased sepsis risk (crude OR 1.48; 95% CI 1.45–1.51) compared to least deprived quintile. Strong predictors for sepsis included antibiotic exposure in prior 2 months, being house bound, having cancer, learning disability, and diabetes mellitus. Severely frail patients had a case fatality rate of 42.0% compared to 24.0% in non-frail patients (adjusted OR 1.53; 95% CI 1.41–1.65). Sepsis cases with recent prior antibiotic exposure died less frequently compared to non-users (adjusted OR 0.7; 95% CI 0.72–0.76). Case fatality strongly decreased over calendar time. Conclusion Given the variety of predictors and their level of associations for developing sepsis, there is a need for prediction models for risk of developing sepsis that can help to target preventative antibiotic therapy.