Hepatitis C virus (HCV) replicon-harbouring cell lines possessing interferon (IFN)-resistant phenotypes have recently been established. These were divided into two classes: partially IFN resistant and highly IFN resistant. Here, the viral and cellular factors contributing to the IFN resistance of HCV replicon-harbouring cells were evaluated. The results revealed that cellular factors rather than viral factors contributed to a highly IFN-resistant phenotype. The possibility of genetic abnormality of the factors involved in IFN signalling was investigated. As a result, nonsense mutations and deletions in type I IFN receptor genes (IFNAR1 and IFNAR2c) were found in replicon-harbouring cells showing a highly IFN-resistant phenotype, but rarely appeared in cells showing a partially IFN-resistant phenotype. Furthermore, similar genetic alterations were also found in IFN-resistant phenotype, replicon-harbouring cell lines obtained additionally by IFN-beta treatment. Moreover, it was shown that ectopic expression of wild-type IFNAR1 in IFN-resistant phenotype, replicon-harbouring cells possessing the IFNAR1 mutant restored type I IFN signalling.