Glucocorticoids have been an important part of maintenance immunosuppressive therapy following orthotopic liver transplantation (OLT). However, long-term daily glucocorticoid use is associated with a high incidence of unpleasant side effects. In an effort to minimize side effects while maintaining adequate immunosuppression, we have treated 48 adult patients with low dose alternate-day prednisone, 15 mg q.o.d. Pre-OLT diagnoses included primary biliary cirrhosis (16 patients), alcoholic liver disease (8 patients), sclerosing cholangitis (8 patients), cryptogenic cirrhosis and/or non-A, non-B hepatitis (11 patients), acute hepatic failure (3 patients), and hepatocellular carcinoma and bile duct carcinoma (1 patient each). Conversion to alternate-day prednisone was attempted when patients were clinically stable and the daily prednisone dose was 15 mg. The average interval between OLT and beginning of the conversion to alternate-day prednisone was 38 weeks. The mean time for conversion to alternate-day prednisone was 35 weeks, but decreased as more experience was gained. The mean follow-up was 106 weeks. Cushingoid side effects diminished in all. In 47 of the 48 patients, there were no clinical laboratory or histologic changes suggestive of rejection after the initiation of alternate-day prednisone. A single episode of rejection occurred during the taper. This episode responded promptly to increased glucocorticoid therapy, and the patient was easily converted to alternate-day prednisone at a later date. There was no increase in concurrent immunosuppressives dosage after the conversion. Alternate-day prednisone is effective and safe for chronic immunosuppression after OLT in patients receiving cyclosporine and azathioprine.