Objective: To investigate the expression of CDX2 and Villin in gastric mucosal lesions and their clinicopathological significance and diagnostic role. Methods: Ninety cases of gastric mucosa biopsy specimens in total, including 21 cases of chronic gastritis, 22 cases of chronic stomach disease associated with intestinal metaplasia, 25 cases of gastric intraepithelial neoplasia, and gastric carcinoma 22 cases, were collected from our hospital from January 2015 to May 2017. The immunohistochemical methods were used to detect the expression of CDX2 and Villin in the gastric mucosal biopsy tissue. Results: CDX2 and Villin had high expression in patients with intestinal metaplasia, gastric intraepithelial neoplasia and gastric cancer, and their positive rate was significantly higher than that of chronic gastritis, the differences were statistically significant (P<0.01). CDX2 was positively correlated with Villin (P<0.01). Conclusion: Both CDX2 and Villin are expressed in the intestinal metaplasia, gastric intraepithelial neoplasia and gastric cancer tissue, suggesting that the two may play an important role in the occurrence of gastric cancer (especially gastrointestinal carcinoma), at the same time, it can be used as the basis for the auxiliary diagnosis of gastric cancer and precancerous lesions (especially morphology is difficult to determine).