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Recurrent hepatitis C is one of the greatest challenges to liver transplantation. In a double-blind, multicenter, randomized trial, Neoral formulation (NEO) was compared to Sandimmune (SIM) in de now liver transplant recipients. Aim: To determine the incidence and severity of recurrent hepatitis C and its impact on outcome in patients on NEO or SIM immunosuppression. Methods: 325 patients from 15 centers were randomized (1:1) to receive either NEO or SIM; 111 patients were hepatitis C positive (serology) pretransplant of which 60 received NEO and 51 received SIM. Initially, patients were treated with intravenous cyclosporine therapy and were converted early to oral therapy at 10 mg/kg/day, titrated to a target trough level according to protocol. Steroid and adjunctive therapy were according to local protocols. All patients were followed for two years. Recurrence of hepatitis C was defined on the basis of a liver biopsy performed on protocol or for abnormal liver tests. Results: Patient demographics were comparable between the two groups. Patients were treated with study medication for a mean of 516 days for NEO vs. 492 for SIM. The percentage of patients with histologic recurrent hepatitis C at two years was NEO 48.1% vs. SIM 50.0% (p=NS). Time to recurrence was comparable between the two treatment groups. The dose and trough level of cyclosporine at the time of recurrence of hepatitis C were NEO 4.5mg/kg/day (276 ng/ml) and SIM 5.2mg/kg/day (302 ng/ml), respectively (p=NS). In the NEO and SIM hepatitis C groups. respectively, the incidence of rejection was 55% vs. 51%, histologic severity of rejection (moderate-to-severe) was 26% vs. 22%, and the use of OKT3 for steroid- resistant rejection was similar between the two groups. The severity of recurrent hepatitis C, assessed by ALT levels (mean±STD) at one year. was NEO 84±54 IU/L vs. SIM 101±80 W/L (p=NS). Two-year patient survival rates for patients with recurrent hepatitis C in the two groups were NEO 84% and SIM 87% (p=NS). Conclusion: Although the NEO formulation provides greater exposure to cyclosporine than the SIM formulation, the incidence, severity, and survival of recurrent hepatitis C were similar in both treatment arms.