Ezrin and E-cadherin have been known to play a role in tumor metastasis. However, the association between the expression of ezrin and E-cadherin in breast cancer patients remains unclear. In the present study, we investigated the expression of ezrin and E-cadherin in 275 breast cancer and 80 control patients with benign hyperplasia, using tissue microarray-based immunohistochemistry (IHC). Ezrin expression was higher, while that of E-cadherin was lower in breast cancer than in control samples. Ezrin expression was negatively correlated with E-cadherin expression in a subpopulation of breast cancer patients with a high expression of ezrin [ezrin(high)] and a low expression of E-cadherin [E-cad(low)]. The cytoplasmic expression of E-cadherin [E-cad(c)] occurred significantly more frequently in ezrin(high) breast cancer than in ezrin(low) breast cancer. The expression level of ezrin was significantly higher in breast cancer with E-cad(c) than that with a membrane expression of E-cadherin [E-cad(m)]. Ezrin(high) or E-cad(low) expression was more associated with lymph node metastasis, and shorter overall survival (OS) and disease-free survival (DFS) in breast cancer patients. E-cad(c) was more associated with lymph node metastasis and shorter OS and DFS compared with E-cad(m). The combined expression of ezrin(high) and E-cad(low) or ezrin(high) and ezrin(c) was more associated with lymph node metastasis and poor prognosis. In addition, the multivariate Cox regression analysis revealed that lymph node metastasis and ezrin(high) expression were independent prognostic factors for shorter OS and DFS in breast cancer patients. The results of the present study suggested that ezrin promotes breast cancer metastasis via the regulation of E-cadherin expression.