Half of the population of genotype 1 HCV is resistant to current pegylated-interferon-alpha (PEG-IFN-alpha) and ribavirin therapy. The resistance to IFN therapy is an urgent problem, especially in patients with genotype 1 HCV infection. However, sensitivities among HCV strains to anti-HCV reagents including IFNs have not been thoroughly addressed. Here, we established three different subgenomic replicons (1B-4, 1B-5, and KAH5 strains) in addition to our previously established replicon (O strain). We comparatively examined the sensitivities of four replicons to IFN-alpha, IFN-gamma, IFN-lambda, cyclosporine A, and fluvastatin. Among the replicons, the 1B-4 and KAH5 replicons were the most sensitive and resistant, respectively to IFN-lambda (EC(50): 1.50 ng/ml vs. 8.50 ng/ml) and fluvastatin (EC(50): 2.82 microM vs. 7.87 microM), although these replicons possessed similar features in terms of genetic distance from the O strain, HCV RNA expression levels, and sensitivity to IFN-alpha (EC(50): 1.44 IU/ml vs. 1.37 IU/ml) and cyclosporine A (EC(50): 0.71 microg/ml vs. 0.96 microg/ml). These replicons are thus useful tools for examining the mechanism of anti-HCV activity, especially in IFN-lambda and statins.