BACKGROUND/AIMS: The Cdx-1 and Cdx-2 genes are intestinal transcription factors that may be involved in the regulation of proliferation and differentiation of intestinal epithelial cells. The Cdx-1 and Cdx-2 are expressed in the epithelium of the small intestine and colon but not in the normal epithelium of the esophagus and stomach. Conversely, aberrant Cdx-2 expression is often observed in the esophagus and stomach. We investigated the expression and role of Cdx-2 in intestinal metaplasia and gastric adenocarcinoma. METHODS: The gastric tissues obtained endoscopically were analyzed by the reverse transcriptase-polymerase chain reaction and histology. The Cdx-1 and Cdx-2 mRNA expression was confirmed and analyzed according to updated Sydney classification. Then, immunohistochemical study with monoclonal anti-Cdx-2 antibody was performed with gastric adenocarcinoma obtained by surgical resection. RESULTS: The prevalence of Cdx-1 and Cdx-2 mRNA expression was significantly higher in mucosa with intestinal metaplasia than mucosa without intestinal metaplasia. In immunohistochemical study, nuclear staining of Cdx-2 was strong in metaplastic mucosa, but weak in adjacent normal gastric mucosa (p<0.001). The expression of Cdx-2 in gastric adenocarcinoma was lower than in metaplastic mucosa (p<0.001). The Cdx-2 expression was also detected in 97% of intestinal type gastric adenocarcinoma and 61.5% of diffuse type gastric adenocarcinoma (p=0.003). CONCLUSIONS: Aberrant expression of Cdx-2 is observed in intestinal metaplasia and a subset of gastric adenocarcinoma, which is predominant in intestinal-type gastric adenocarcinoma. Therefore, Cdx-2 may play an important role in gastric carcinogenesis, especially in intestinal type adenocarcinoma.