Tumor protein D52 (TPD52) has been indicated to be involved in tumorigenesis of various malignancies. But its role in hepatocellular carcinoma (HCC) is unknown. This study aimed to explore the expression of TPD52 in HCC samples and cell lines using real-time quantitative PCR, western blotting, and immunohistochemistry. The prognostic value of TPD52 in HCC was also analysed. Meanwhile, the mechanism of TPD52 in hepatocarcinogenesis was further investigated by western blotting, immunohistochemistry, over-express and knockdown studies. We found that TPD52 expression was significantly decreased in the HCC tissues and HCC cell lines. TPD52 expression was significantly correlated with tumor-nodes-metastasis (TNM) stage. Kaplan-Meier survival curves showed that high TPD52 expression was associated with improved overall survival (OS) and disease-free survival (DFS) in HCC patients. Multivariate analysis indicated that TPD52 expression was an independent prognostic marker for the OS and DFS of patients. In addition, TPD52 expression was positively correlated with p21 and p53 expression, and was negatively correlated with MDM2, BCL2 and P-GSK-3β expression in HCC. In conclusions, our findings suggested that TPD52 is a potential tumor suppressor in HCC. It may be a novel prognostic biomarker and molecular therapy target for HCC.