Infection with hepatitis C virus (HCV) is currently treated with interferon-α( IFN-α) , but the molecular mechanismby which IFN inhibits HCV replication still remains elusive. Therefore, in this study, we attempted to elucidate the possible mechanismfor the IFN-inducible protein, Viperin, against HCV. Over-expression of Viper in could significantly down-regulate intracellular levels of HCV protein and RNA in both the replicon and HCVcc systems. Membrane flotation analysis indicated that expression of Viperin could interfere with the association of HCV NS3 and NS5A with the lipid raft, resulting in increased sensitivity of these two proteins to the treatment of non-ionic detergent. Furthermore, Viperinwas able to interact with FPPS because co-transfection of Viperin with FPPS could partially reverse the anti-HCV effects of Viperin in replicon cells. The above results indicate a possible novel mechanismof IFN-induced antiviral activity, that is, over-expression of Viperin can interfere with the microdomain of intracellular lipid raft and, therefore, further disrupt the stability of viral replicase complex to inhibit its functions.