To assess the long-term safety of an immunosuppressive regimen without corticosteroids, we retrospectively evaluated 42 long-term (greater than 1 year) survivors of orthotopic cardiac transplantation. We determined the incidence of (1) conversion of the immunosuppressive regimen from cyclosporine and azathioprine alone (group I) to cyclosporine, azathioprine, and prednisone (group II), (2) late acute graft rejection (defined as occurring at greater than 1 postoperative year), and (3) major postoperative complications related to corticosteroids. Of the 42 patients who were started on cyclosporine and azathioprine, 48% remained in group I, and 52% converted to group II. Forty-five percent of group II patients were able to taper and discontinue prednisone in 15.6 +/- 2.2 months. Among the patients on long-term corticosteroid-free immunosuppression, the incidence of late rejection was 2.1% per endomyocardial biopsy. The incidence of late infectious episodes was not significantly different between the two groups of patients, although diabetes mellitus and hypercholesterolemia were more prevalent in group II than in group I. These data suggest that cardiac transplant recipients who chronically remain on corticosteroid-free immunosuppression represent a select group of patients with an acceptably low risk of late graft rejection and associated reduction of potential risk factors of accelerated coronary artery disease.