Hepatitis C is a major cause of chronic hepatitis worldwide and current medical treatment options are limited.Interferon y (IFN-γ) is an important proinflammatory cytokines with antiviral activity in HCV infection.However, the mechanism of IFN-γ in anti-HCV infection remains unclear.In this study, we investigated the role of IFN-γ in HCV infection of polarized Caco-2 cells using cell culture-derived HCV (HCVcc).We found that down-regulation of claudin-1 (CLDN1) expression induced by IFN-γ treatment disrupted epithelial barrier function in a time-dependent manner as demonstrated by measurement of transepithelial electrical resistance and dextran permeability; results from confocal microscopy and Western blot analysis showed that the reduction of CLDN1 expression was associated with significant changes in the distribution of CLDN1, CD81 and SR-B1 in Caco-2 cells following treatment of IFN-γ; subsequent infection assays revealed that IFN-y treated cells showed decreased susceptibility to HCVcc infection.Our results suggest IFN-y may be crucial in the inhibition of HCV infection by regulating CLDN1 expression and HCV receptors distribution.