Aberrant expression of HOXC6 has been reported in several malignant tumors, yet little is known about the value of HOXC6 in invasion and prognosis of hepatocellular carcinoma (HCC). HOXC6 expression was positively correlated with high AFP level, liver cirrhosis, larger tumor, vascular invasion and BCLC stage. Kaplan-Meier analysis revealed that HOXC6 was an independent predictor for overall survival (OS) and time to recurrence (TTR). In addition, HOXC6 status could act as prognostic predictor in different risk subgroups. Moreover, HOXC6 maintained its prognostic value in different ability of invasiveness. Furthermore, combination of HOXC6 and serum AFP could be a potential predictor for survival in HCC patients. Additionally, further study showed that HOXC6 may promote invasion of HCC by driving epithelial-mesenchymal transition (EMT). Knockdown of HOXC6 significantly decreased the migration and invasion of HCC cells and changed the expression pattern of EMT markers. An opposite expression pattern of EMT markers was observed in HOXC6-transfected cells. In addition, immunohistochemistry and RT-PCR results further confirmed this correlation. In conclusion, HOXC6 contributes to invasion by inducing EMT pathway and predicts poor prognosis of HCC. HOXC6/AFP expression may help to distinguish the different risks of HCC patients after hepatectomy.