HIV-associated nephropathy (HIVAN) is a renal disease characterized clinically by heavy proteinuria and renal failure and morphologically by severe and rapidly evolving focal and segmental glomerulosclerosis, tubular necrosis, interstitial edema, and ultrastructural cellular inclusions. In an attempt to elucidate its pathogenesis, we evaluated the role of direct viral (HIV) infection of renal epithelium with the use of a cDNA probe for viral nucleic acid and an immunoperoxidase-labeled antibody to p24 core protein. In 10 of 11 kidneys with HIVAN, nucleic acid was localized to glomerular and tubular epithelium, while only 2 of 4 kidneys from HIV-infected patients with immune complex glomerulonephritis were similarly affected, but with considerably less cellular involvement. Kidneys from patients with acquired immune deficiency syndrome but without renal disease had only rare cellular positivity. In all instances, the cDNA probe was more sensitive than anti-p24 immunoperoxidase. These data suggest a role for direct HIV infection of renal epithelial cells in the initiation and/or progression of HIV-associated nephropathy.