The purpose of this study was to evaluate early (6-12 days) prednisone withdrawal in cyclosporine- and azathioprine-treated renal transplant recipients. Patients, including 8 recipients of live-related donor kidneys and 59 recipients of cadaver donor kidneys, were prospectively randomized to receive maintenance prednisone (PRED) therapy or not (NOPRED) in addition to antilymphocyte globulin, cyclosporine, and azathioprine. Rejection episodes were initially treated with methylprednisolone pulses, and OKT3 monoclonal antibody was used to treat steroid resistant rejections that were verified by biopsy. NOPRED patients were declared protocol failures and returned to PRED therapy if they sustained 2 steroid-sensitive rejection episodes in the first 3 months or an OKT3-treated rejection at any time. Patient and graft survival for the LRD patients in both treatment categories were 100% at 12 months. Patient and graft survival for CAD recipients at one year was 94% and 83% (PRED) and 88% and 77% (NOPRED), respectively. Rejection episodes were more frequent (26 of 32 NOPRED patients vs. 19 of 35 PRED patients P = 0.02) and occurred earlier (4.5 weeks in NOPRED vs. 7.7 weeks in PRED patients) in patients not taking maintenance steroids. Rejection severity was also greater in the NOPRED group, as 15 OKT3-treated rejections occurred in that group whereas only 7 OKT3-treated rejections were observed in the PRED group (P = less than 0.01). The incidence of serious infection was similar in each group. Finally, protocol failure occurred in 40% of the LRD patients and 59% of the CAD patients. These data indicate that initiating maintenance therapy without PRED is safe but is attended by a greater risk of developing rejection. Because of this increased incidence and severity of early rejection episodes in NOPRED patients, we do not advise use of this immunosuppressive strategy in renal transplantation.