To identify the novel genes involved in lipid metabolism and lipid droplet formation that may play important roles in Hepatitis C virus (HCV) propagation, we have screened the small interfering RNA library using cell culture derived HCV (HCVcc)‐infected cells. We selected and characterized the gene encoding farnesyl‐diphosphate farnesyltransferase 1 (FDFT1). siRNA‐mediated knockdown of FDFT1 impaired HCV replication in both subgenomic replicon and HCVcc infected cells. Moreover, YM‐53601, an inhibitor of FDFT1 enzyme activity, abrogated HCV propagation. HCV infection increased FDFT1 protein level but not FDFT1 mRNA level. These results suggest that HCV may modulate FDFT1 protein level to facilitate its own propagation.