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Objective: To explore the influence of the retinoic acid indicible gene-I (RIG-I) on hepatitis C virus (HCV) replication and the molecular mechanism of action of RIG-I. Methods: We constructed an RIG-I expression vector and co-transfected it into Huh-7 cells along with HCV-replicon RNA. We assayed HCV replication and NS5A protein synthesis via real-time polymerase chain reaction (RT-PCR) and western blotting. Also, we performed an enzyme-linked immunosorbent assay (ELISA) to measure the level of interferon (IFN)-α/-β secretion. Additionally, we examined, via western blotting, the phosphorylation state of p38, Erk1/2, and nuclear factor (NF)-kB p65. Results: Overexpression of RIG-1 in Huh-7 cells co-transfected with an HCV-replicon RNA significantly inhibited HCV replication and NS5A protein synthesis. Co-transfected cells had increased production of IFN- α/-β production and had higher levels of phosphorylated p38, Erk1/2, and NF-kB p65. Conclusions: RIG-I significantly inhibits HCV replication and NS5A protein synthesis by inducing type I IFN production. The underlying molecular mechanism for this effect appears to be mediated by increased phosphorylation of NF-kB p65, p38-mitogen-activated protein kinases (MAPK), and Erk1/2. [ABSTRACT FROM AUTHOR]