To study the clinical course and the predictors of outcome in children and adolescents, 39 patients with nephrotic syndrome and primary focal segmental glomerulosclerosis (FSGS) were followed for a mean of 84.6 months. Thirty-six patients were treated with prednisone, either alone or in conjunction with cyclophosphamide. The clinical course was one of sustained remission in 4 patients, frequent relapse in 13, persistent nonnephrotic proteinuria in 5, and persistent nephrotic syndrome in 17; 2 patients had stable renal failure and 8 had progressive renal failure, 5 of them evolving to end-stage renal failure (ESRF). Resistance to prednisone was recorded in 76.6% of patients. The use of cyclophosphamide plus prednisone was of benefit in 42.8% of patients; 22.2% of the prednisone-resistant patients achieved remission of the nephrotic syndrome. A Kaplan-Meier analysis revealed a survival rate of 92% after 5 years, 86% after 10 years, and 76% after 15 years. Using both univariate and multivariate analysis, persistent nephrotic syndrome was associated with progression to ESRF and the remission of proteinuria with maintenance of renal function. As the outcome of the nephrotic syndrome in FSGS is significantly improved by remission of proteinuria, it is conceivable that immunosuppressive medication may be used in conjunction with prednisone in patients with steroid resistance.