The mechanisms leading to viral persistence and hepatocarcinogenesis in hepatitis C virus (HCV) infection are not fully understood. Recently, evidence has been accumulated that HCV viral proteins might interfere with gene expression of host cells. Here, we demonstrate that the amino-terminal portion of HCV NS2 protein inhibits the expression of reporter genes driven by different promoters or enhancer elements and also inhibits hepatitis B virus (HBV) gene expression and HBV DNA replication. The inhibitory effect of HCV NS2 on liver and non-liver-specific promoters and enhancer elements might be relevant for the pathogenesis of chronic HCV infection.