AZA has been reported to cause liver dysfunction in some recipients of solid organ transplants. To assess the safety and efficacy of cyclophosphamide in maintenance immunosuppression in the setting of AZA-induced liver dysfunction, we retrospectively reviewed the records of 320 surviving cardiac transplant recipients in Utah. Cyclophosphamide was substituted for AZA in 29 patients due to elevated liver enzymes. Patients were switched to cyclophosphamide 689 +/- 104 days after transplantation; total follow-up after initiation of cyclophosphamide was 540 +/- 56 days. The dose of cyclophosphamide after 2 and 6 months of cyclophosphamide therapy was 62 +/- 6 mg/day (0.8 +/- 0.1 mg/kg/day) and 48 +/- 5 mg/day (0.6 +/- 0.1 mg/kg/day), respectively, compared with 233 +/- 20 mg/day (2.9 +/- 0.2 mg/kg/day) of AZA. The substitution of cyclophosphamide for AZA was associated with a significant improvement in liver function tests. Liver enzymes decreased by up to 49% (P = 0.027), while serum bilirubin decreased by 58% (P < 0.001). Rejection frequency did not increase; neither corticosteroid nor CsA dosage was altered significantly after the substitution of cyclophosphamide. Significant bone marrow suppression was not observed; specifically, no significant change in white blood cell count or hematocrit occurred. Complications of treatment with cyclophosphamide were few; only 1 patient discontinued cyclophosphamide because of alopecia. We conclude that cyclophosphamide appears to be safe in maintenance immunosuppression, permitting the discontinuation of AZA in patients with AZA-induced hepatic dysfunction without necessitating the augmentation of either corticosteroids or CsA.