Background. Mycophenolate mofetil (MMF) significantly reduces the incidence of acute allograft rejection in renal transplant patients. The effect of adding MMF to the immunosuppressive regimen of patients with established rejection is unknown. The purpose of the current study was to compare the safety and efficacy of the addition of MMF to the treatment regimen of an early first acute cellular rejection. Methods. The study was a double-blind, double-dummy controlled a clinical trial of 221 renal transplant recipients experiencing the first biopsy-proven rejection within 6 months of transplant performed at 15 U.S. and Canadian centers. A total of 113 patients received MMF (1.5 g twice daily) and intravenous corticosteroids, and 108 patients received azathioprine (AZA) (1-2 mg/kg/day) and intravenous corticosteroids. The intravenous corticosteroids in each group consisted of 5 mg/kg/day for 5 days followed by an oral steroid taper. End points for the study were the first use of antilymphocyte therapy, the number of courses of antirejection therapy given during the first 6 months, and graft and patient survival at 1 year. Results. At 6 months, 16.8% of the MMF-treated patients and 41.7% of the AZA-treated patients required at least one course of antilymphocyte therapy (P<0.0001). The number of patients requiring full courses of antirejection therapy for the treatment of rejection was less in the MMF-treated group (24.8%) versus the AZA-treated group (58.3%) (P<0.0001). The proportion of patients with the use of antilymphocyte therapy or treatment failure during the first 6 months was 29.2% vs. 51.9% (P=0.0006) in the MMF versus the AZA groups, respectively. By 1 year after enrollment, 10 patients (8.9%) in the MMF-treated group lost their graft or died versus 16 patients (14.8%) in the AZA-treated group. More patients in the MMF group withdrew because of an adverse event: 20 patients (17.7%) compared with 11 AZA-treated patients (10.2%). Conclusions. MMF administered in combination with pulse corticosteroids significantly decreases the subsequent use of antilymphocyte therapy in the treatment of acute renal allograft rejection. In addition to being a safe and effective prophylactic agent, MMF added to steroids improves the rate of reversal of acute rejection episodes.