Decreased expression of epithelial cadherin (E-cadherin) has been noted to associate with aggressiveness and metastasis of breast cancer. The aim of this study was to examine the effect of C-Terminal EH domain-containing protein 2 (EHD2) expression on E-cadherin and related mechanism in the metastasis of breast cancer. Immunohistochemical analysis was performed in 96 human breast carcinoma samples and the data were correlated with clinicopathologic characteristics. Furthermore, Western blot analysis was performed for EHD2 and E-cadherin in breast carcinoma samples and cell lines to evaluate their protein levels and molecular interaction. We found that the expression of EHD2 was positively related with E-cadherin expression (P < 0.01), moreover, EHD2 expression was significantly correlated with histologic grade (P < 0.01). Meanwhile, E-cadherin expression obtained similar results. Kaplan-Meier survival analysis showed that decreased expression of EHD2 and E-cadherin exhibited a significant correlation with poor prognosis in human breast cancer (P < 0.01). While in vitro, we employed siRNA technique to knock down EHD2 expressions and observed their effects on breast cancer cells growth. EHD2 depletion by siRNA promoted PCNA expression, and it was concurrent with the decreased expression of epithelial marker E-cadherin and the increased expression of N-cadherin by Western blot analysis. Consistent with these observations, the suppression of EHD2 in breast cancer cells remarkably promoted cellular proliferation and migration. On the basis of these results, we suggested that EHD2 can inhibit the metastasis of human breast cancer by regulating the EMT key markers E-cadherin and N-cadherin.