Mycophenolate mofetil (MMF), a new immunosuppressant that selectively inhibits proliferation of T and B lymphocytes, may reduce the frequency and severity of acute graft rejection. Acute graft rejection is the leading cause of graft loss in cadaveric renal transplantation. The purpose of this randomized, double-blind, multicenter study was to evaluate the efficacy and safety of MMF for the prevention of acute rejection episodes in adult patients during the first 6 months after renal transplantation. A total of 499 patients who were to receive a primary cadaveric renal allograft as their first transplant were randomized to receive MMF 1.0 g b.i.d. (MMF 2 g treatment group), MMF 1.5 g b.i.d. (MMF 3 g treatment group), or aza-thioprine 1-2 mg/kg/day. CsA, corticosteroids, and antithymocyte globulin (ATGAM®) were administered as part of a quadruple sequential induction protocol. The primary efficacy endpoint was biopsy-proven rejection or treatment failure (defined as graft loss, death, or premature withdrawal from the study for any reason) during the first 6 months after transplant. All enrolled patients were included in the primary analyses of efficacy on the basis of intent to treat. The 495 patients who received study drug were included in the safety and secondary efficacy analyses. Biopsy-proven acute rejection episodes or treatment failure occurred in 41.6% of patients in the azathioprine group compared with 31.1% (P=0.0015) and 31.3% (P=0.0021) of patients in the MMF 2 g and 3 g treatment groups, respectively. Time to first biopsy-proven rejection episode or treatment failure was significantly longer for MMF 2 g versus azathioprine (P=0.0036) and MMF 3 g versus azathioprine (P=0.0006). First biopsy-proven rejection alone occurred in 38.0% of patients who received azathioprine compared with 19.8% and 17.5% of patients who received MMF 2 g and 3 g, respectively. Patients in the azathioprine group received a greater number of full courses of antirejection treatment as compared with the MMF 2 g and MMF 3 g groups (44.5%, 24.8%, and 21.1%, respectively). The use of antilymphocyte agents to treat rejection was greater in the azathioprine group (20.1%) compared with the MMF 2 g group (10.3%) and the MMF 3 g group (5.4%). At 6 months after transplant, graft and patient survival were similar in all 3 treatment groups. The incidence and types of adverse events were similar among treatment groups, with the exception of a higher incidence of diarrhea, certain other infrequent gastrointestinal adverse events, clinically important leukopenia, and tissue-invasive CMV disease in the MMF groups, particularly in the MMF 3 g group. Three patients who received MMF developed lymphoma/lym-phoproliferative disorder. This study demonstrated that MMF administered at a dosage of 2 g or 3 g daily, in combination with maintenance CsA and corticosteroids as triple therapy following ATGAM® induction therapy, is more effective than an otherwise identical regimen that includes azathioprine instead of MMF in preventing acute allograft rejection in first cadaveric renal transplant patients. This regimen also has an acceptable adverse event profile. The MMF 3 g dosage was considered to be somewhat less well tolerated than the MMF 2 g dosage. © 1995 by Williams & Wilkins.