We recently reported the effects of combined interferon-/cyclosporin A treatment. Cyclophilins are associated with HCV replication and bind cyclosporin A. Which cyclophilins are closely associated with HCV replication remains controversial. In this study, several cyclophilins were found to be essential host factors for HCV replication and HCV replication was rescued by overexpression of cyclophilin A in the presence of cyclosporin A. Methods: We evaluated the effect of cyclosporin A and its analogues on the replication of HCV in vitro using several types of HCV replicon. The gene expression of representative cyclophilins and Pin-1 was knocked down using small interfering RNA2 (siRNA) to identify cyclophilins associated with HCV replication. The specificity of the effect of siRNA was confirmed by western blot analysis. The effect of overexpression of cyclophilins on HCV replication in the presence of cycloporin A was also studied. Results: Cyclosporin A and its analogues suppressed HCV replication in a dose dependent manner. Cyclophilin F, cyclophilin LC1 and cyclophilin LC2 as host factors which are closely associated with HCV replication, in addition to the previously reported cyclophilin A. Knockdown of chclophilin B showed little effect on HCV RNA replication. Cyclophiln-dependent HCV replication varied among the three HCV replicon cell-lines used.