PR (PRDI-BF1 and RIZ) domain protein 5 (PRDM5) is a newly identified member of the PRDM family and has been suggested to play important roles in tumor development. However, the association between PRDM5 expression and the clinical characteristic of hepatocellular carcinoma (HCC) is not well investigated. In this present study, one-step quantitative reverse transcription-polymerase chain reaction (qPCR) with 10 fresh-frozen HCC and immunohistochemistry (IHC) analyses in 90 HCC cases were performed respectively to explore the relationship between PRDM5 expression and the clinicopathological items of HCC. The results showed that the expressions of PRDM5 were significantly decreased in HCC tissues than in corresponding non-cancerous tissues (P < 0.05). The IHC information implied that the PRDM5 protein expression in HCC was statistically correlated with pathological grade (P = 0.014), T (P = 0.001) and TNM stage (P = 0.001). Both survival analysis and Kaplan-Meier curve demonstrated that higher PRDM5 protein level (P = 0.048) was substantially associated with the favorable prognosis of patients with HCC. The data suggested that PRDM5 may be identified as a novel prognostic biomarker for HCC.