CTHRC1 expression is involved in invasion and metastasis in various tumors. However, the molecules involved in its signaling pathways in hepatocellular carcinoma (HCC) remain elusive. The migration and invasion abilities of HCC cells stably expressing CTHRC1 were assessed in vitro and in vivo with a mouse model. Moreover, signaling pathways involved in invasion and metastasis were analyzed. CTHRC1 was abundantly expressed in HCC cell lines and HCC tissues. CTHRC1 was also detectable in the serum of HCC patients, compared with non-tumor controls. CTHRC1 mRNA was positively correlated with large tumor size (p <0.003), Edmondson differentiation grade (p <0.0001), microvessel invasion (p <0.05), intrahepatic metastasis (p <0.005), and HCC stage (AJCC, p <0.0001). Ectopic expression of CTHRC1 in HepG2 cells promoted cell migration and invasiveness in vitro, and promoted tumor metastasis in a lung metastasis mouse model. Knockdown of CTHRC1 by short hairpin RNA (shRNA) in HCC cells suppressed migratory and invasive abilities. Growth factor-mediated CTHRC1 expression promoted cancer cell invasiveness and metastasis through activation of CREB/Snail signaling, which induced EMT change and MMPs expression. Therefore, CTHRC1 and its downstream molecules may be potential therapeutic targets for HCC invasion and metastasis.