Focal segmental glomerulosclerosis associated with human immunodeficiency virus nephropathy (HIVFGS) involves glomeruli, tubules, and interstitium. Its pathogenesis is unknown, but HIV peptides may be critical in its development. Human immunodeficiency virus peptides and peptide-antibody complexes are immunomodulatory, and are associated with apoptosis in lymphoid cells. To determine whether apoptosis is present in HIVFGS, renal biopsy specimens of eight patients with HIVFGS were compared with those of 10 patients with idiopathic focal glomerulosclerosis (FGS) using the Apoptag kit (Oncor, Gaithersburg, MD), which detects single cell apoptosis in formalin-fixed tissue by staining 3' nucleosome fragments with digoxigenin-labeled nucleotides after terminal deoxynucleotidyl transferase enzyme treatment. Apoptosis was scored per glomerulus, in total renal tissue sectioned, and in tubules and interstitium per square millimeter using a computerized digital image analyzer. There was no difference between the number of apoptotic cells per glomerulus or per square millimeter of interstitium in patients with FGS and HIVFGS. There were greater numbers of tubular apoptotic cells per square millimeter (2.1 +/- 0.9 v 0.15 +/- 0.08; P = 0.03) in HIVFGS compared with idiopathic FGS. The difference between apoptotic cells per total square millimeter of renal tissue (2.8 +/- 1.2 v 0.7 +/- 0.3) approached significance (P = 0.066). Apoptosis may be associated with the pathogenesis of HIV nephropathy and may be an important determinant of the tubular disease in HIVFGS.