A prospective randomized drug trial was carried out on 59 patients with confirmed membranoproliferative glomerulonephritis (MPGN). The treatment group (27 patients) received cyclophosphamide, coumadin, and dipyridamole for 18 months, and the control group (32 patients) received no specific therapy. Complications of the renal disease such as hypertension and fluid retention were treated similarly in both groups. Entrance criteria included confirmed renal pathology demonstrating either types I or II MPGN, a corrected creatinine clearance (CCr) of less than 80 ml/min/1.73 m2, and/or proteinuria greater than 2 g/day. Actuarial survival was not different between the treatment and the control groups in either MPGN type and was 85% in type I and 90% in type II at 2 years. The change in renal function, as measured by both the slope of CCr and the plasma creatinine reciprocal (1/Cr) at 6, 12, and 18 months was not significantly different between treatment and control groups in either types I or II when tested by both parametric and nonparametric analysis. The age, sex, and initial level of CCr did not influence the rate of decline. Control and treatment group proteinuria was not different at any time point in either types I or II MPGN. The small numbers of type II MPGN cases do not give sufficient power to allow conclusions regarding this therapy in type II. We can conclude that this treatment is ineffective in altering the natural history of type I MPGN.