Aberrant expression of pepsinogen C (PGC) has been observed in human cancers. However, its role in hepatocellular carcinoma (HCC) remains to be established. The goal of this study is to illustrate PGC expression and to evaluate its clinical relevance in HCC. PGC expression was examined in 75 pairs of HCC and adjacent non-tumor tissues using tissue microarray. The correlations between its expression and clinical parameters were also analyzed. PGC overexpression was significantly associated with larger tumor size (≥5 cm; =0.017) and incomplete encapsulation (<0.0001). Cox regression model demonstrated that PGC expression and tumor size were independent prognostic factors for overall survival (OS) and disease-free survival (DFS) in HCC. The subgroup analysis by Kaplan-Meier uncovered that OS and DFS were much worse in high PGC level group than in low PGC level group with large tumor size subgroup, while no difference of OS was noted between the two groups with low tumor size subgroup. PGC plays a tumorigenesis role in HCC progression, which may lead to a novel insight to the potential biomarker and novel therapeutic strategies for HCC patients.