Recently, overexpression of EphA2, a member of the Eph family of receptor tyrosine kinases, has been reported in several cancers. Reduced expression of E-cadherin, an intercellular adhesion molecule of epithelial cells, has been reported to be associated with aggressive clinicopathological phenotypes in various cancers. In epithelial cells, EphA2 and E-cadherin co-localize to sites of cell-cell contact, and it has been shown that E-cadherin regulates EphA2. This study aimed to clarify the relationship between the expression of the EphA2 and E-cadherin proteins and clinicopathological characteristics, with reference to the expression levels of both EphA2 and E-cadherin, in patients with colorectal cancer. We performed immunohistochemical staining of EphA2 and E-cadherin with EphA2 and E-cadherin monoclonal antibodies in samples from 194 primary lesions of colorectal cancer. The expression level of EphA2 had a statistically significant relationship with liver metastasis, lymphatic vessel invasion and clinical stage (p=0.0477, 0.0316 and 0.0467, respectively). In addition, the positivity rate of EphA2 was significantly higher in primary lesions with lymph node metastasis than in those without metastasis (p=0.0014). However, the expression level of E-cadherin had an inverse relationship with both differentiation level of the tumor and lymphatic vessel invasion (p=0.0430 and 0.0320, respectively). Furthermore, a significant relationship between the expression of EphA2 and E-cadherin was observed. In conclusion, our study revealed that the overexpression of EphA2 protein in colorectal carcinoma tissue correlates closely with cancer progression and hematogenous and lymphogenous metastasis, suggesting that both EphA2 and E-cadherin may play an important role in tumor metastasis in colorectal cancer.