We prospectively examined the effect of treatment with intravenous cyclophosphamide in patients with steroid-resistant nephrotic syndrome. Twenty-four patients (minimal change disease in 11, focal segmental glomerulosclerosis in 9, and mesangioproliferative glomerulonephritis in 4), who did not show remission of proteinuria despite treatment with 8 weeks of oral prednisolone and six intravenous pulses of dexamethasone, were studied. Cyclophosphamide was administered intravenously, at a dose of 750 mg/m(2) once a month for 6 months; therapy with alternate-day prednisolone was continued. The mean (SD) age at treatment was 7.8 (4.0) years; 18 patients had initial resistance and 6 had late resistance. At the end of 6 months treatment, 7 (29.2%) patients each had complete remission (absent proteinuria, normal serum albumin) and partial remission (1-2+ proteinuria, normal serum albumin). Ten (41.6%) patients showed no response to therapy. The mean time to complete or partial remission, after initiation of treatment with cyclophosphamide, was 2.4+/-1.7 months and 2.7+/-1.8 months, respectively. Most responders (85.8% complete and 57.2% partial responders) achieved remission by the third dose of pulse cyclophosphamide. More patients with late resistance (50%) compared with initial resistance (22.2%) achieved complete remission. Partial remission was transient and lasted for a mean duration of 6.4+/-3.5 months. Serious infections were observed during therapy in 5 patients. On long-term follow-up, 5 (20.8%) patients were in remission, while nephrotic-range proteinuria or end-stage renal disease was seen in 17 (70.8%). Findings from the present study suggest that therapy with intravenous cyclophosphamide has limited efficacy in inducing sustained remission in patients with initial corticosteroid resistance. Sustained remission is likely to occur in a significant proportion of patients with late resistance and those with absence of significant tubulointerstitial changes on renal histology.