Aim To investigate the expression and clinical significance of ephrin type-A receptor 2 and epithelial-mesenchymal transition-related proteins in primary hepatocellular carcinoma. Methods Tissues from 52 primary hepatocellular carcinomas and 12 human normal liver tissues were detected for expression of ephrin type-A receptor 2, E-cadherin, and N-cadherin by immunochemistry. Cinicopathological features of hepatocellular carcinoma and tumor recurrence after operation were studied for the association with these molecular expressions and E-N cadherin switch. Results Increased expressions of ephrin type-A receptor 2 and N-cadherin and reduced expression of E-cadherin were significantly detected in hepatocellular carcinoma compared with normal liver tissues. Univariate analysis showed that there were close associations between unfavorable clinicopathological features and expressions of ephrin type-A receptor 2, E-cadherin, N-cadherin, and E-N cadherin switch. Ephrin type-A receptor 2 and E-cadherin expressions were confirmed as independent prognostic factors when corrected with age, gender, AFP, HBsAg, liver cirrhosis, tumor size, nodules, capsule, portal vein invasion, cell differentiation, and TNM stage. Conclusions The overexpression of ephrin type-A receptor 2 protein is correlated with the number of tumors, capsular integrity, portal vein cancer thrombus and clinical stages. Epithelial-mesenchymal transition regulated by ephrin type-A receptor 2 is involved in the aggressive clinicopathological features and prognosis, suggesting that the receptor may play an important role in the progression and metastasis of hepatocellular carcinoma.