Diabetes mellitus is the most common cause of treated end-stage renal disease (ESRD), and diabetic hemodialysis patients have a high mortality rate. To identify differences in risk of septicemia among diabetic and nondiabetic hemodialysis patients, we examined the incidence, risk factors, and mortality for septicemia in a large sample of the US hemodialysis population. We performed a longitudinal cohort study of the incidence and risk factors for hospitalized cases of septicemia in diabetic and nondiabetic hemodialysis patients using baseline data from the US Renal Data System case-mix severity study with 7-year follow-up from hospitalization and death records. Independent risk factors for septicemia were assessed using Poisson regression. Independent effect of septicemia on mortality was assessed using Cox proportional hazards analysis. Over 7 years, 11.1% of nondiabetic patients and 12.5% of diabetic patients experienced at least one episode of septicemia. Older age and low serum albumin were independent risk factors for septicemia in all patients. In diabetics, white race, peripheral vascular disease, and hemodialyzer reuse, particularly in type 1, were independent risk factors. In nondiabetics, coronary artery disease, cerebrovascular disease, and temporary and permanent catheters were associated with an increased risk. In both groups, patients who experienced an episode of septicemia had twice the risk of death from any cause and an eightfold risk of death from septicemia. Septicemia occurs equally frequently and carries a marked increased risk of death in both nondiabetic and diabetic hemodialysis patients. Improving nutritional status and minimizing the use of catheters might help ameliorate the risk of septicemia. In diabetics, aggressive treatment of peripheral vascular disease might help reduce the risk of septicemia. Further research to elucidate potential mechanisms for variations in risk for septicemia according to race and hemodialyzer reuse practices are warranted in diabetic patients.