Mycophenolate mofetil (RS-61443), a derivative of mycophenolic acid, is a new immunosuppressive agent that inhibits de novo purine synthesis in activated lymphocytes. In a clinical trial of mycophenolate mofetil in the treatment of recurrent or persistent heart rejection, 17 patients 0.6 to 104 months (median 5.4 months) after transplantation received a daily oral dose of mycophenolate mofetil of 3000 mg, with seven patients increasing to 3500 mg daily. Azathioprine was routinely discontinued at the start of mycophenolate mofetil treatment. One patient in shock from acute rejection required retransplantation before starting mycophenolate mofetil and died 68 days later of cytomegalovirus sepsis. Another patient died 72 days after mycophenolate mofetil of protracted multisystem failure (present before mycophenolate mofetil). One patient required early cessation of mycophenolate mofetil, and the other 14 patients were alive and well 5 to 10 months after initiating mycophenolate mofetil treatment. Three patients required transient dose reduction and one patient required discontinuation of mycophenolate mofetil because of nausea, diarrhea, or abdominal cramps. No other clinical side effects were noted. Frequency of rejection decreased from 0.67 rejection episodes per patient per month before mycophenolate mofetil to 0.27 rejection episodes per patient per month after mycophenolate mofetil (p < 0.0001). Frequency of infection was unchanged after mycophenolate mofetil (p = 0.9). Renal function was not affected by mycophenolate mofetil (creatinine clearance 1.8 mg/dl before mycophenolate mofetil vs 1.7 mg/dl after mycophenolate mofetil; p = 0.3). Bilirubin and aspartate aminotransferase levels remained normal during mycophenolate mofetil treatment. White blood cell count (7000/mm3 versus 6600/mm3 after mycophenolate mofetil; p = 0.6) and platelet count (p = 0.1) were unchanged during the 2 months before and after the start of mycophenolate mofetil. In conclusion, as an immunosuppressive agent, mycophenolate mofetil is an effective adjunct in the treatment of recurrent or persistent rejection, with no discernible early renal, hepatic, or bone marrow toxicity. Gastrointestinal symptoms are the only apparent early side effects. This preliminary experience with mycophenolate mofetil supports an expanded role of mycophenolate mofetil in maintenance immunotherapy after heart transplantation.