Clinical and pathologic findings in the kidneys of 30 consecutive acquired immunodeficiency syndrome (AIDS) autopsies and in 34 consecutive renal biopsies performed on HIV infected patients at our institution between 1983 and 1987 were studied. To determine if the lesions of HIV-associated nephropathy have morphologic specificity, a subgroup of 13 biopsies with a diagnosis of HIV-associated nephropathy (HIVN) were compared to 13 biopsies each of heroin-associated nephropathy (HAN) and of idiopathic focal segmental glomerulosclerosis (IFSGS) matched for patient age, proteinuria and serum creatinine. A diagnosis of HIVN was made in 1 of 30 (3.3%) AIDS autopsies and 26 of 34 (76.5%) renal biopsies. When compared to HAN and IFSGS, HIVN had more globally "collapsed" glomeruli (P less than 0.001), less glomerular hyalinosis (P less than 0.02), more severe visceral epithelial cell swelling (P less than 0.05), more numerous visceral epithelial cell droplets (P less than 0.002), more prevalent and severe tubular microcystic dilatation (P less than 0.02), and tubular cell degenerative changes (P less than 0.001). Focal glomerular electron-dense deposits were present in 14 of 26 cases. Tubuloreticular inclusions were extremely numerous in glomerular and interstitial capillary endothelial cells as well as in interstitial leukocytes (P less than 0.001). Granular degeneration of nuclear chromatin was present in 10 of 26 cases. Nuclear bodies were more numerous in tubular and interstitial cells of HIVN (P less than 0.01), particularly type 3 (P less than 0.001). Reversal of tissue T4/T8 ratio was observed. We conclude that while no single morphologic feature of HIVN is specific, the combination of clinical and pathologic findings is quite distinctive and permits a presumptive diagnosis of HIVN in otherwise asymptomatic carriers.