In the United States, infection is second to cardiovascular disease as the leading cause of death in patients with end-stage renal disease (ESRD), and septicemia accounts for more than 75% of this category. This increased susceptibility to infections is partly due to uremia, old age, and comorbid conditions. Although it is intuitive to believe that mortality caused by sepsis may be higher in patients with ESRD compared with the general population (GP), no such data are currently available. We compared annual mortality rates caused by sepsis in patients with ESRD (U.S. Health Care Financing Administration 2746 death notification form) with those in the GP (death certificate). Data were abstracted from the U.S. Renal Data System (1994 through 1996 Special Data request) and the National Center for Health Statistics. Data were stratified by age, gender, race, and diabetes mellitus (DM). Sensitivity analyses were performed to account for potential limitations of the data sources. Overall, the annual percentage mortality secondary to sepsis was approximately 100- to 300-fold higher in dialysis patients and 20-fold higher in renal transplant recipients (RTRs) compared with the GP. Mortality caused by sepsis was higher among diabetic patients across all populations. After stratification for age, differences between groups decreased but retained their magnitude. These findings remained robust despite a wide range of sensitivity analyses. Indeed, mortality secondary to sepsis remained approximately 50-fold higher in dialysis patients compared with the GP, using multiple cause-of-death analyses; was approximately 50-fold higher in diabetic patients with ESRD compared with diabetic patients in the GP, when accounting for underreporting of DM on death certificates in the GP; and was approximately 30-fold higher in RTRs compared with the GP, when accounting for the incomplete ascertainment of cause of death among RTRs. Furthermore, despite assignment of primary cause-of-death to major organ infections in the GP, annual mortality secondary to sepsis remained 30- to 45-fold higher in the dialysis population. Patients with ESRD treated by dialysis have higher annual mortality rates caused by sepsis compared with the GP, even after stratification for age, race, and DM. Consequently, this patient population should be considered at high-risk for the development of lethal sepsis.