To assess the effectiveness of an intensive immunosuppressive regimen on the nephrotic syndrome due to mixed membranous and mesangial lesions, we studied 18 patients with nephrotic syndrome and miscellaneous histologic features characterized by mesangial proliferation and sclerosis, non-specific basement membrane changes such as thickening, fraying and scalloping, in the absence of extensive immune complex deposition by immunofluorescence. The patients were treated with an immunosuppressive regimen that combined prednisone and cyclophosphamide for at least 6 months with the following schedule: 1) induction with prednisone daily 250 to 750 mg i.v. for 3 to 8 days, plus cyclophosphamide 100 to 200 mg p.o. daily; 2) maintenance with prednisone 100 to 200 mg p.o. in alternate days for 30 to 75 days, and cyclophosphamide as before; 3) tapering, with prednisone in alternate day regimen, reduced on average by 25 mg every month, plus cyclophosphamide as before; 4) discontinuation of cyclophosphamide and slow withdrawal of prednisone. Treatment lasted on average 9 months, with an average cumulative dose of prednisone of 9.2 g and of cyclophosphamide of 26.7 g. At the end of treatment, 14 patients had a complete remission and 4 remained stable. On longer follow-up, one out of these 4 patients, who had renal failure before treatment, subsequently progressed to end-stage renal disease. Nine patients relapsed after an average remission of 6 years. Eight of them remitted completely on a repeat cycle. One patient refused the retreatment and progressed to end-stage renal disease within one year. After an average follow-up of 7.3 +/- 1.1 years, plasma creatinine for the whole group had fallen from 138 +/- 26 to 103 +/- 20 mumol/l and proteinuria from 6.7 +/- 0.7 to 0.4 +/- 0.2 g/d (p < 0.001). In conclusion, in patients with these forms of nephrotic syndrome this immunosuppressive regimen is highly effective in inducing remission, in preventing progression to end-stage renal disease and in treating relapses.