Most heart transplant recipients develop hypercholesterolemia, the cause of which is poorly understood. To test the hypothesis that corticosteroids contribute to the hypercholesterolemia, we reviewed 117 consecutive heart transplant recipients who survived more than 4 months, of whom 51 (44%) required and 66 (56%) did not require maintenance corticosteroids, chronic immunosuppression maintained with cyclosporine and azathioprine only. Fasting serum cholesterol levels were measured every 3 months and were found to be 21% to 26% lower during the first 18 months after heart transplantation in the group that did not require chronic corticosteroid administration (p less than 0.001). Beginning 3 months after transplantation, average serum cholesterol levels ranged from 199 +/- 8 mg/dl to 211 +/- 9 mg/dl in the corticosteroid-free group compared with 262 +/- 8 mg/dl to 272 +/- 8 mg/dl in patients requiring corticosteroid maintenance immunosuppression. Because serum cyclosporine levels did not differ between the groups, a contribution by cyclosporine to posttransplant hypercholesterolemia could not be substantiated. Although the hypercholesterolemia that occurs after heart transplantation is undoubtedly multifactorial, corticosteroid administration contributes importantly to its development.