Human immunodeficiency virus-associated nephropathy (HIVAN) develops more often in HIV-infected blacks than whites. Blacks also show marked familial clustering of other causes of end-stage renal disease (ESRD), particularly diabetes mellitus-, hypertension-, and systemic lupus erythematosus-associated ESRD. We compared the family history of ESRD in 201 blacks with ESRD caused by HIVAN (cases) to that of 50 HIV-infected blacks without renal disease (controls) to determine whether HIV-associated ESRD shows familial aggregation. Cases were identified using the Southeastern Kidney Council/ESRD Network 6 Family History of ESRD database. Cases initiated dialysis between September 1993 and October 1998. Controls were consecutively identified, HIV-infected blacks with serum creatinine concentrations of 1.3 mg/dL or less and no proteinuria, treated in an infectious disease clinic during September 1998. Cases and controls had similar mean ages and family sizes. First- or second-degree relatives with ESRD were reported by 24.4% of the cases compared with 6% of the controls (P = 0.004). Logistic regression analysis, controlling for sex, family size, and age, showed cases were 5.4 times more likely than controls to have close relatives with ESRD (P = 0.007). The 49 HIVAN cases who reported a positive family history had a mean of 1.2 additional relatives with ESRD per case (60 total relatives with ESRD). HIVAN was not listed as the cause of ESRD in any of the 27 relatives who underwent dialysis in Network 6 facilities. We conclude that ESRD clusters in the families of nearly 25% of blacks initiating renal replacement therapy for HIVAN. This familial aggregation of ESRD appears to be independent of HIV infection. Although environmental factors cannot be excluded, it is possible an inherited susceptibility to renal failure is present in many blacks with HIV infection who subsequently develop nephropathy.