The aim of this study was to compare the long-term effect of tacrolimus and cyclosporine therapies on serum cholesterol levels in liver transplant recipients. We retrospectively studied 127 consecutive adult liver transplant recipients who survived for at least 1 year after transplantation. Basal immunosuppression consisted of cyclosporine plus prednisone in 100 patients and tacrolimus plus prednisone in 27 patients. Hypercholesterolemia was defined as a fasting serum cholesterol level greater than 220 mg/dL. Mean follow-up was 39 months. No statistical significance was found between cyclosporine- and tacrolimus-treated patients regarding age, sex, diagnosis, and previous cholesterol levels; both groups were similar. Significantly more tacrolimus-treated patients were steroid free in the first and second year of follow-up (tacrolimus, 37% and 63%; cyclosporine, 13% and 32%, respectively; P <.01). In the third year of follow-up, this difference was not significant (77% v 56%). The overall incidence of hypercholesterolemia was 34.6% (44 patients). At the end of the study, hypercholesterolemia was found in 24 of 51 and 14 of 70 patients with and without steroids, respectively (P <.002). Also, mean cholesterol levels were 224 +/- 70 and 191 +/- 48 mg/dL before and after steroid withdrawal, respectively, P <.001. Hypercholesterolemia was found in 43.7% of the patients during cyclosporine plus prednisone therapy compared with 46.1% of the patients during tacrolimus plus prednisone therapy (P <.9). Greater mean cholesterol levels were found in the cyclosporine group, particularly in the second and third years of follow-up (P <.01). Hypercholesterolemia was found in 22% of the patients during cyclosporine monotherapy compared with 15% during tacrolimus monotherapy (P <.5). No differences were found in mean cholesterol levels during follow-up when both monotherapy groups were compared. In conclusion, a lower incidence of hypercholesterolemia was achieved in tacrolimus-treated patients, mainly when steroids were still part of the immunosuppressive treatment.