The aim of this study is to investigate the expression of pancreatic progenitor cell differentiation and proliferation factor (PPDPF) and its relationship with clinicopathological factors in hepatocellular carcinoma (HCC).A total of 135 patients diagnosed with HCC who underwent curative surgery were enrolled in this study. The expression of PPDPF was examined by real time-polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry. The prognostic value for each sample was explored.Both RT-PCR and western blot revealed PPDPF expression was upregulated in HCC. Higher PPDPF expression was also observed in HCC (54.07%) detected by immunohistochemistry (IHC), which was significantly associated with tumors size (P = .003), Edmondson-Steiner Grading (P = .021), recurrence (P = .010), and Diolame complete (P = .023). Patients with higher PPDPF expression had increased cancer progression and poorer prognosis than those with lower expression (P = .043). Multivariate analysis indicated PPDPF as an independent prognostic factor (P = .014).Aberrance PPDPF expression might be a useful predictor and could serve as a potential therapeutic target for HCC.