At our center, we have performed liver transplantation since 1995 with a rapid-taper steroid protocol (weaning steroids by day 14 posttransplantation). Beginning in 2000, we further reduced the use of corticosteroids to 3 days and added sirolimus to our immunosuppressive regimen. We report our experience with 39 patients who underwent liver transplantation with either tacrolimus or cyclosporin A (Neoral; Novartis Pharmaceuticals Corp., Summit, NJ) and sirolimus, with a 3-day tapered dose of corticosteroids. Thirty-two patients received a cadaveric graft and 7 patients received a right hepatic lobe from a living donor. All patients initially were administered either tacrolimus (0.1 mg/kg/d) or cyclosporin A (10 mg/kg/d) and sirolimus (6 mg/d for 1 day, followed by 2 mg/d), in addition to methylprednisolone on the first 3 days (1, 0.5, and 0.5 g/d) after transplantation. Patients were administered corticosteroids for presumptive or biopsy-proven evidence of acute cellular rejection (methylprednisolone, 1, 0.5, and 0.5 g on 3 successive days). Seventeen patients were administered tacrolimus and 22 patients were administered cyclosporin A. Six patients were excluded from analysis because they were administered sirolimus for less than 2 weeks. Mean duration of follow-up was 124 days. Patient survival was 36 of 39 patients (92%), and graft survival was 35 of 39 grafts (89%). Ten of 33 patients (30%) experienced 12 episodes of rejection (7 biopsy proven, 5 presumptive) compared with 70% in historical controls (P <.01). OKT3 was required in 1 of 33 patients (3%) compared with 37% in controls (P <.01). Twenty-six of 33 patients (79%) were not administered prednisone, and 7 of 33 patients (21%) were administered prednisone for reasons other than rejection. Posttransplantation, there was no significant change in values for creatinine, glucose, aspartate aminotransferase, bilirubin, cholesterol, and white blood cell counts. Platelet counts were significantly reduced, and hematocrits were significantly elevated (P <.05). Liver transplantation may be successfully performed with minimal use of corticosteroids by using sirolimus and either tacrolimus or cyclosporin A. Despite the absence of prednisone from our immunosuppressive protocol, the incidence of rejection and OKT3 use was lower than in historical controls. Patient and graft survival rates were identical to those of historical controls. The findings in this report will serve as the basis for a formal trial evaluating the efficacy of sirolimus in liver transplantation.