Background. Mycophenolate mofetil (MMF) prolongs allograft survival in experimental animals, prevents acute rejection in humans, and has recently been approved for use in renal transplantation in combination with cyclosporine. Tacrolimus (Prograf) has been shown to be effective for the prevention and treatment of allograft rejection in liver transplantation. However, there has been limited experience with the combination of tacrolimus and MMF in liver transplantation. Methods. This retrospective pilot study examined the results in 130 primary, consecutive, adult liver transplants under two separate immunosuppressive protocols. Patients in the study group received MMF (1 g p.o. b.i.d.), tacrolimus (0.1 mg/kg p.o. b.i.d.), and a standard steroid taper. MMF was also tapered and then discontinued within 3 months of transplantation. A historical control received tacrolimus (0.15 mg/kg p.o. b.i.d.) and the same steroid taper. Results. Pretransplant demographics, including creatinine, were not significantly different between the groups. The 6-month patient and graft survivals of 96.3% (control) versus 92.0% (study) were not significantly different. The incidence of acute rejection was 45.0% in the control group versus 26.0% in the study group (P=0.03). The study group had a lower incidence of rejection (mean episodes/patient ± SEM): 0.28 ± 0.07 vs. 0.61 ± 0.10 (P=0.007). All of the study group members responded to high-dose steroids. In the control group, three patients required monoclonal antibody therapy and two patients required the addition of MMF. The incidence of cytomegalovirus was similar in the study group and the control group (13.8% vs. 10.0%, P=NS). Early renal function was better preserved in the tacrolimus/MMF group (mean creatinine ± SEM): 1.09 mg/dl ± 0.05 vs. 1.51 mg/dl ± 0.08 at 30 days, P=0.0001. The study design required dosing with less tacrolimus (mean mg/day ± SEM), which was achieved at 1 week (23.2±0.7 vs. 13.5 ± 0.5); 1 month (18.7 ± 0.8 vs. 11.4 ± 0.5); 3 months (14.5 ± 0.6 vs. 9 ± 0.5); and 6 months (11.6 ± 0.6 vs. 8.2 ± 0.6); P=0.0001, for all time points. Conclusions. Combination therapy with tacrolimus and MMF may significantly reduce the incidence of acute liver allograft rejection, allow a significant reduction in tacrolimus dosage, and decrease the incidence of nephrotoxicity. Long-term analysis will be necessary to assess any increased risk of opportunistic infections.