SOX (high mobility group) genes play an important role in a number of developmental processes. Potential roles of SOXs have been demonstrated in various neoplastic tissues as tumor suppressors or promoters depending on tumor status and types. The aim of this study was to investigate the function role of SOXs in the human hepatocellular carcinoma (HCC). The gene expression changes of SOXs in HCC tissues compared with those in noncancerous hepatic tissues were detected using real-time quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) analysis and immunohistochemistry. In addition, we identified the gene SOX10 that was significantly upregulated in HCC by QRT-PCR analysis and immunohistochemistry. Furthermore, we discovered that SOX10 promoted cancer cell proliferation in vitro, and SOX10 expression correlated with elevated β-catenin levels in HCC, and β-catenin function was required for SOX10's oncogenic effects. Mechanistically, SOX10 facilitates TCF4 to bind to β-catenin and form a stable SOX10/TCF4/β-catenin complex and trans-activate its downstream target gene. SOX10 mutations that disrupt the SOX10-β-catenin interaction partially prevent its function in tumor cells. All in all, SOX10 is a commonly activated tumor promoter that activates Wnt/β-catenin signaling in cancer cells of HCC.