Cyclosporine A (CSA) has potent effects against hepatitis C virus (HCV) in vitro, but its clinical efficacy after liver transplantation (LT) is uncertain. We evaluated the impact of CSA and tacrolimus (TAC) with or without concomitant interferon (IFN) therapy on serum HCV titers in a chimeric mouse model of HCV infection. Six groups of HCV-infected mice received only the vehicle, IFN, CSA, CSA and IFN, TAC, or TAC and IFN for 4 weeks. The quantitative HCV polymerase chain reaction levels were determined after 1, 2, and 4 weeks of drug administration. There were no significant differences in the HCV titers after 4 weeks of treatment between the non–IFN-treated groups (log HCV titers: 3.5 ± 0.3 for the vehicle group, 4.4 ± 0.6 for the CSA group, and 4.3 ± 0.4 for the TAC group, P = 0.3). Although IFN had a consistent effect of reducing HCV titers across the groups, there was no significant impact of CSA on HCV levels when it was used alone or in combination with IFN at any time point. The 4-week HCV titers were as follows: 3.2 ± 0.3 for the IFN group, 4.7 ± 0.4 for the CSA/IFN group, and 4.0 ± 0.5 for the TAC/IFN group (P = 0.07). The CSA/IFN and TAC/IFN groups did not differ significantly (P = 0.6). Six of the 7 animals in the IFN group (85.7%) had an HCV titer decline ≥ 1 log, whereas in the test groups (CSA/IFN and TAC/IFN), 6 of 9 animals (66.7%) achieved a 1-log decline in the HCV titer (P = 1). Using this animal model, we could find no evidence supporting the routine use of CSA after LT in HCV-infected patients. Liver Transpl 18:38–44, 2012. © 2011 AASLD.