To investigate the possible molecular pathogenesis of hepatocellular carcinoma (HCC) induced by HCV infection, CD81-Huh7 cell was transfected by HCV-JFH1 RNA as described in our previous studies. Cells were collected 10, 50, 100 and 150 days after the HCV RNA transfection and were passaged every 3-4 days. PTTG1 mRNA and protein expressions were detected by Real time PCR and Western Blot. The phosphorylated Erk kinase (p-Erk) and the total Erk1/2 protein level were measured by Western blot. MAPK/Erk inhibitor (PD98059) was applied to block the phosphorylation of Erk1/2. HCV was inhibited by IFN. It is found that the levels of PTTG1 mRNA and protein are significantly increased at above time point in HCV transfected cells as compared to the untransfected cells. Parallel with PTTG1, the p-Erk is significantly increased in the transfected groups as compared with the untransfected groups. The inhibition of HCV has significantly decreased the expression of PTTG1 and the phosphorylation of MAPK/Erk1/2; MAPK/Erk1/2 inhibitor has significantly decreased the PTTG1 expression. The HCV infection activates MAPK/Erk1/2 pathway and leads to the increase of oncogenic PTTG1 over-expression, which may be one of the pathogenesis of the HCV related HCC development.