Objective To study the expression of sex-determining region Y-box 4 (SOX4) in hepatocellular carcinoma (HCC) and its relationship with clinicopathological features and prognosis of HCC. Methods The differential expression of SOX4 in HCC was studied through analying and mining the public database of tumor genes by bioinformatics method, and the relationship between SOX4 expression and clinicopathological characteristics was analyzed; the relationship between SOX4 expression and prognosis of HCC patients was analyzed by Kaplan-Meier method; and SOX4-related biological processes and signal pathways in HCC were explored by Gene Set Enrichment Analysis (GSEA). Results The expression level of SOX4 mRNA in HCC tissues was significantly higher than that in the adjacent tissues (P<0.01), and was significantly correlated with tumor stage and tumor size (P<0.01, P<0.05). The overall survival and recurrence-free survival of HCC patients in SOX4 low-expression group were longer than those of patients in SOX4 high-expression group (both P<0.01), and showed the same prognostic trend in different stages of HCC. Multivariate Cox regression analysis showed that the expression level of SOX4 was an independent prognostic factor of HCC patients (P<0.01). SOX4 played an oncogenic role in HCC by regulating DNA replication, inositol-requiring enzyme 1 (IRE1)-mediated unfolded protein response, mitotic cell cycle arrest, tumor protein p53 activity, Wnt signaling pathways and so on. Conclusion The expression of SOX4 is increased in HCC tissues, and is related to poor prognosis.