A region associated with sensitivity to interferon has been identified in the nonstructural protein 5A(NS5A) of hepatitis C virus(HCV) genotype 1b. The region spans amino acid residues 2209 to 2248(NS5A2209-2248). While complete response was not obtained in the patients with HCV whose NS5A2209-2248 sequences were identical to that of HCV-J (wild type), all patients with HCV of 4 to 11 amino acid substitutions (mutant type) achieved complete response. We designed this region as the interferon sensitivity determining region(ISDR). Recently, a subgenomic HCV replicon system was established, and reported to replicate efficiently and continuously in human hepatoma Huh-7 cells. However, HCV replicon needs amino acid mutation, called as adaptive mutations, in NS5A for efficient replication. These findings demonstrate that the genetic structure of the NS5A domain is critical in HCV replication.