Background. Mycophenolate mofetil (MMF) has been shown to have promise in short-term liver transplantation graft rescue studies. The purpose of this study was to evaluate the long-term efficacy and safety of MMF in liver transplant patients who had failed cyclosporine (CsA)-based conventional immunosuppression. Methods. Nineteen orthotopic liver allograft recipients were converted from azathioprine to MMF in combination with CsA and prednisone in this prospective, open-labeled, single-center, graft rescue, pilot study. Six patients were taken off CsA when MMF was initiated. A 4- year patient follow-up is reported here. Patients were considered to have failed CsA-based immunosuppression either for refractory rejection, chronic rejection, or severe CsA neurologic toxicity. Results. Twelve patients had complete histologic resolution, two had partial resolution, and three had worsening of their rejection. Thirteen patients had a complete biochemical response; one had a partial response and four had worsening of their rejection. Two patients had no histologic and one no biochemical follow-up. Of the six patients treated with MMF and prednisone alone, four had complete resolution of rejection without recurrence. The majority of adverse reactions were gastrointestinal [nausea and/or vomiting (n=5); diarrhea (n=8); gastritis, duodenitis, or esophagitis (n=4); and ulcers (n=2)] or bone marrow suppressive [leukopenia (n=9), anemia (n=6), and thrombocytopenia (n=5)]. Conclusions. MMF seems to be an effective alternative immunosuppressive in patients failing CsA-based conventional therapy. MMF may be of particular benefit in patients who do not tolerate CsA or tacrolimus. The long-term safety profile is similar to that of other immunosuppressives.