HLA-A, B, and DR antigen frequencies were studied in a group of 57 patients to determine possible inborn susceptibility to idiopathic focal segmental glomerulosclerosis (FSGS). There were 34 white patients and 23 black patients, most of whom had nephrotic syndrome and later developed renal failure. HLA-DR4 was significantly increased in both patient groups when compared with their respective control groups. This association has not been previously reported. Of note, the association with DR4 was most striking in patients with adult onset disease (in blacks, relative risk equals 5.2; in whites, relative risk equals 5.8). No other antigen was increased in both patient groups but HLA-A28 was increased in blacks. These data support the notion of genetic predisposition to focal segmental glomerulosclerosis in two different ethnic groups.