Abstract: To study relationship between CLDN18 gene expression and the clinicopathologic features of gastric cancer ( GC ). Methods: A tissue microarray was made and immunohistochemistry was performed to detect the expression of claudin-18 protein. Real-time polymerase chain reaction was conducted to examine mRNA expression of CLDN18 gene. Results: Expression of claudin-18 protein in GC was significantly downregulated and was correlated with histologic types and extent of invasion, which was greatly decreased in the intestinal-type and intramuscular infiltration of GC than in the diffuse-type and the extramuscular extension, respectively. There was a gradual downregulation of claudin-18 expression from the mucosa to the front of the invasion. Claudin-18 expression was higher in the mucosa than at the front of invasion. Of the 34 cases with advanced GC without downregulation of claudin-18 expression in mucosa, 28 had claudin-18 downregulation as GC developed to the front of the invasion. In the 28 cases, the incidences of the diffuse-type GC, extramuscular infiltration, lymph node metastasis, and non-cardiac GC were higher compared with the intestinal-type, intramuscular, non-metastatic, and cardiac GC. CLDN18 mRNA expression was downregulated in 20 of the 52 GC cases. The relative expression was associated with the infiltration and size of the tumors. Conclusion: Downregulation of claudin-18 expression is involved in the progression of disease, and in maintaining the phenotype of gastric adenocarcinoma.