Background: Cyclophosphamide can decrease proteinuria and improve renal function in patients with idiopathic membranous nephropathy, but has a high risk of side effects. We studied whether mycophenolate mofetil (MMF) could be a reasonable alternative with fewer side effects. Study Design: Clinical trial with historic controls. Settings & Participants: 32 cases and 32 controls with idiopathic membranous nephropathy and renal insufficiency at multiple centers. For comparison, we selected matched historic controls treated with cyclophosphamide. Intervention: MMF, 1 g twice daily, for 12 months versus cyclophosphamide, 1.5 mg/kg/d, for 12 months. Both groups also received intermittent methylprednisolone and alternate-day prednisone. Outcomes & Measurements: Serum creatinine, proteinuria, and side effects during and after treatment. Results: Median follow-up was 23 months (range, 11 to 46 months). Median serum creatinine levels were 1.8 mg/dL (159 μmol/L) in both groups at baseline and 1.4 mg/dL (124 μmol/L) in the MMF group versus 1.3 mg/dL (115 μmol/L) in the cyclophosphamide group at 12 months (P = 0.4). Proteinuria values at baseline and 12 months were protein of 8.40 and 1.41 g/d in the MMF group versus 9.19 and 1.13 g/d in the cyclophosphamide group (P = 0.5 at 12 months), respectively. Cumulative incidences of remission of proteinuria at 12 months were 66% in the MMF group versus 72% in the cyclophosphamide group (P = 0.3). Five patients (16%) in the MMF group versus none in the cyclophosphamide group had disease that did not respond to therapy (P = 0.05). Twelve patients (38%) experienced a relapse and 9 patients (31%) were re-treated in the MMF group compared with 4 (13%) and 2 patients (6%) in the cyclophosphamide group (P < 0.01 and P = 0.024, respectively). Side effects occurred in 24 patients (75%) in the MMF group and 22 patients (69%) in the cyclophosphamide group (P = 0.6). Limitations: Nonrandomized control group, short duration of follow-up. Conclusions: A 12-month course of MMF decreased proteinuria and improved renal function in the majority of patients, but did not appear as effective or better tolerated than cyclophosphamide. Long-term data and randomized controlled trials are needed to ascertain the efficacy of MMF in patients with idiopathic membranous nephropathy.