African Americans have higher overall incidence rates of end-stage renal disease (ESRD) compared with American whites. Hypertensive nephrosclerosis (HN), nephropathy secondary to diabetes mellitus types I and II, and chronic glomerulonephritis (CGN) all occur more frequently in African Americans. To explore the possibility that hereditary factors may play a role in the increased risk of ESRD in African Americans, the family history of 131 African American hemodialysis patients (cases) was compared with 115 age-, sex-, and race-matched non-ESRD controls. Odds ratios (ORs) were calculated to define the prevalence of a relative with ESRD among cases versus controls. Chi-square values were estimated from a log-linear model, while controlling for gender, to test for significance of ORs. Forty percent (12/30) of HN cases, 35% (18/51) of type II diabetes mellitus-induced renal failure cases, and 13% (5/38) of CGN cases had a first-, second-, or third-degree relative with ESRD. The presence of a first-degree relative with ESRD increased an African American's risk for developing ESRD ninefold (OR, 9.13; 95% confidence interval [CI], 2.6 to 31.8; P < 0.001). The presence of a first- or second-degree relative increased the risk fivefold (OR, 5.23; 95% CI, 2.2 to 12.3; P < 0.0002). First-, second-, or third-degree relatives with ESRD were more prevalent among cases with ESRD due to hypertension and type II diabetes mellitus compared with CGN (P ≤ 0.05). Gender differences among the ORs were nonsignificant (P > 0.2) and socioeconomic class (level of education and income) did not differ markedly between cases and controls. A strong familial association of ESRD exists in African Americans, particularly in those with hypertension and type II diabetes mellitus-induced renal disease. An inherited predisposition to renal injury is likely to be present in some African American families, although shared environmental exposure may contribute to the observed risk.