C-terminal binding protein 2 (CtBP2) is a transcriptional co-repressor that promotes cancer cell migration and invasion by inhibiting multiple tumor suppressor genes that contribute to cell mobility and adhesion. In this investigation, we showed thatCtBP2 expression was increased significantly in HCC tissues when compared to matched normal adjacent liver tissues. We also showed that CtBP2 expression is associated with worse HCC patient prognosis after liver resection. CtBP2 over-expression induced epithelial-mesenchymal transition (EMT) in Huh7 cells and, correspondingly, silencing CtBP2 suppressed EMT in MHCC97H cells. ChIP assays revealed that GLI1 increased CtBP2 transcription by directly binding its promoter. Furthermore, interaction of CtBP2 and Snail Family Zinc Finger 1 (SNAI1), both of which were found to be positively regulated by GLI1, was confirmed by Co-IP assay. SNAI1 knockdown revealed that SNAI1 was essential for CtBP2 induction of the EMT phenotype of HCC cells, and CtBP2 knockdown reversed GLI1-SNAI1 driven EMT in Huh7 cells. Finally, in vivo experiments demonstrated that enhanced CtBP2expression promoted HCC xenograft growth and induced EMT. In conclusion, CtBP2 may serve as a prognostic marker for post liver resection HCC and may play a role during GLI1-driven EMT as a transcriptional co-repressor of SNAI1.