Recurrent hepatitis C virus (HCV) remains a problematic cause of morbidity and mortality for liver transplant patients. Immunosuppression including calcineurin-inhibitors has been implicated in the acceleration of recurrent HCV. Recent studies suggest that outcomes may be better with cyclosporine (CSA-ME) compared to tacrolimus (TAC), but the data are inconclusive. We retrospectively analyzed data received from the United Network for Organ Sharing on 8809 chronic HCV liver transplant recipients receiving either cyclosporine microemulsion (CSA-ME) or tacrolimus (TAC) as maintenance immunosuppression prior to discharge. We analyzed patient death, graft failure, failure due recurrent disease and acute cellular rejection (ACR) for CSA-ME versus TAC treated patients. Three-year unadjusted patient and graft survival rates were 76.8% and 71.5%, respectively, in the CSA-ME group versus 79.9% and 75.0% in the TAC group. Propensity score-adjusted results suggest CSA-ME treated patients are at increased risk of patient death and graft failure [Hazards ratio (HR) = 1.17; 95% CI = 1.01-1.36 and HR = 1.19; 95% CI = 1.04-1.35, respectively] and biopsy-confirmed AR (HR = 2.03; 95% CI = 1.54-2.67) compared to TAC treated patients. These results provide evidence to reconsider the targeted administration of CSA-ME to HCV-infected liver transplant recipients.