Steroid-free maintenance immunosuppression is frequently initiated early after transplantation. There is concern that later steroid withdrawal, particularly after previous rejection, may cause more serious rejection. To determine the safety of gradual weaning from steroid maintenance, 68 patients (more than 6 months from transplantation) were weaned from 5 mg/day by decreasing the daily dose by 1 mg each month, with monthly biopsies. Asymptomatic moderate rejection occurred in 13 compliant patients. Rejection with hemodynamic compromise occurred in two patients with documented medication noncompliance, who were excluded from further analysis. Successful weaning without rejection was possible in 53 of 66 (80%) compliant patients. Compared with the rejection group, there were no differences in the number of women, previous rejection episodes, or time from transplantation. All moderate rejection episodes responded to oral steroid pulse therapy. The two serious rejections after noncompliance responded to OKT3. There were no symptoms from steroid withdrawal that required taper alteration. We conclude that regardless of previous rejection episodes, weaning from maintenance steroids can be attempted safely if guided by frequent biopsy procedures, but compliance is critical.