The aims of this study are to investigate the relationship between p39 expression and clinicopathological parameters of hepatocellular carcinoma (HCC) and to evaluate the prognostic value of p39 for HCC patients. Real-time quantitative PCR and immunohistochemistry was used to measure p39 expression in tumor and adjacent nontumor samples. Relationships of p39 expression with clinical parameters and patient survival were analyzed. Real-time quantitative RT–PCR showed that the quantity of p39 mRNA in cancerous tissue was significantly lower than that in nontumor tissue (P < 0.001). Immunohistochemistry data confirmed that p39 protein was reduced in 64% of HCC. p39 expression was not influenced by chronic alcohol exposure or cirrhosis. Reduction in p39 was correlated with the HBV (P = 0.039), HCV (P = 0.011), and histological grade (P < 0.001). HCC patients with lower p39 expression had poorer overall survival rate than that with high expression (HR, 2.868; 95% CI, 1.451–5.670; P = 0.002). Together with other results, these results reveal that p39 expression was reduced in HCC tissue. p39 could be a useful clinical prognostic marker for hepatocellular carcinoma patients.