AIM: To investigate the expression of hypoxia-inducible factor (HIF)-2a/endothelial PAS domain protein 1 (EPAS1) in hepatocellular carcinoma (HCC). METHODS: Expression of HIF-2a/EPASl was investigated immunohistochemically on paraffin-embedded sections from 97 patients with HCC. To further confirm that HIF-2a/EPASl in HCC tissues also correlated with angiogenesis, a parallel immunohistchemistry study of vascular endothelial growth factor (VEGF) was performed on these 97 cases. RESULTS: HIF-2a/EPASl could be detected in 50 of 97 cases (51.6%), including 19 weakly positive (19.8%), and 31 strongly positive (31.1%), the other 47 cases were negative (48.4%). The expression of HIF-2a/EPASlwas significantly correlated with tumor size, capsule infiltration, portal vein invasion, and necrosis. A parallel immunohistochemical analysis of VEGF demonstrated its positive correlation with capsule infiltration, portal vein invasion, and HIF-2a/EPASl overexpression, which supported the correlation of HIF-2a/EPASlup-regulation with tumor angiogenesis. No apparent correlation was observed between HIF-2a/EPASl and capsular formation, presence of cirrhosis, and histological grade. CONCLUSION: HIF-2a/EPASl is expressed in most of HCC with capsular infiltration and portal vein invasion, which indicates a possible role of HIF-2a/EPASl in HCC metastasis.