Context.-Diabetes is a frequent cause of end-stage renal disease (ESRD). However, the degree of risk is uncertain. Objective.-To determine the relative risk (RR) of ESRD related to diabetes in the United States. Design.- Nonconcurrent prospective cohort study. Participants.-A total of 332 544 men aged 35 to 57 years from 18 US cities screened in 1973 to 1975 for participation in the Multiple Risk Factor Intervention Trial (MRFIT). Main Exposure.-Diabetes mellitus defined by self-reported use of medication for diabetes at baseline. Main Outcome.-Incident ESRD through 1990 assessed from a national ESRD registry and by surveillance for death from renal disease. Results.-Over an average follow-up of 16 years, there were 136 cases of ESRD in 5147 diabetic men and 678 cases in 327 397 nondiabetic men. Age-adjusted incidence of all-cause ESRD in the diabetic men was 199.8 per 100 000 person- years compared with 13.7 per 100 000 person years in their nondiabetic counterparts (RR, 12.7; 95% confidence interval [Cl], 10.5-15.4). Diabetic men were also at higher risk for ESRD ascribed to causes other than diabetes (RR=4.3; 95% Cl, 3.2-5.9). With simultaneous adjustment for age, ethnicity, income, blood pressure, serum cholesterol level, and history of myocardial infarction, diabetic men remained at higher risk for all-cause ESRD (RR, 9.0; 95% Cl, 7.4-11.0), ESRD ascribed to diabetes (RR, 92.3; 95% Cl, 64.6-131.9), and ESRD ascribed to nondiabetic causes (RR, 3.0; 95% Cl, 2.2-4.1). Conclusion.-Diabetes mellitus is a strong independent risk factor for ESRD, even for ESRD ascribed to causes other than diabetes. Improvements in the prevention and control of diabetes should produce substantial reductions in ESRD incidence.