The long-term outcome of a group of children with nephrotic syndrome who showed a histological lesion of focal segmental glomerular sclerosis (FSGS) during the course of their illness were studied. Of 25 children studied, a complete follow-up ranging from 3-19 yr was available in 24. Distinct groups (2) could be identified. The 1st group was characterized by steroid resistance (SR) from onset; the 2nd group was initially steroid sensitive (SS) and had a histological lesion of minimal change which evolved into FSGS. SR patients had a mean age of 7.7 .+-. 3.7 yr while SS patients were 3.5 .+-. 2.5 yr old (P < 0.01). There were more females (11 of 14) in the SR group than in the SS group (3 of 10; P < 0.02). Incidence of hematuria was higher in SR patients (9 of 14) than SS patients (2 of 10; P < 0.05). SR patients exhibited a greater degree of growth retardation at the end of the follow-up period (9 of 13 compared to 1 of 8 SS patients; P < 0.02). SR patients reached end-stage renal failure earlier (2.3 .+-. 1.3 yr) than SS patients (10 .+-. 5.8 yr; P < 0.01) after the initial biopsy. Of 13 kidneys transplanted into 9 SR patients, recurrence of FSGS was noted in 2 allografts. Of 4 kidneys transplanted into 2 SS patients, recurrence was seen in 1. Overall recurrence rate of FSGS in allografts was 17.6%. The 2 varieties of FSGS occurring in nephrotic patients may be distinct nosologic entities rather than 1 disease with varied manifestations.