To investigat the clinical significance of Ezrin in the development and progression of gastric cancer. Immunohistochemistry was employed to analyze Ezrin expression in 436 clinicopathologically characterized gastric cancer cases. Ezrin protein levels were up-regulated in gastric cancer lesions compared with adjacent noncancerous tissues. Positive expression of Ezrin correlated with age, size of tumor, location of tumor, depth of invasion, vessel invasion, lymph node and distant metastasis and TNM stage. In stages I, II and III, the 5 year survival rate of patients with a high expression of Ezrin was significantly lower than those in patients with low expression. In stage IV, Ezrin expression did not correlate with the 5 year survival rate. Further multivariate analysis suggested that the depth of invasion, lymph node and distant metastasis, TNM stage, and up-regulation of Ezrin were independent prognostic indicators for the disease. Expression of Ezrin in gastric cancer is significantly associated with lymph node and distant metastasis, and poor prognosis. Ezrin protein could be useful markers to predict tumor progression and prognosis.