BACKGROUND/AIMS: The caudal-related homeobox transcription factor, Cdx2, plays an important role in proliferation and differentiation of intestinal epithelial cells. Its expression is confined to normal and neoplastic intestinal epithelium. We evaluated Cdx2 expression in advanced colorectal cancers to determine the correlation between Cdx2 expression and clinicopathologic characteristics. METHODS: Four hundreds twenty consecutive colorectal cancers were included in the study. Cdx2 expression was investigated by immunohistochemistry using tissue microarrays constructed from surgically resected specimens. 145 invasive breast cancers, normal tissues from gastric mucosa, liver, lung, kidney and ovary were used as control. Nuclear staining was considered to be positive and the result was divided into 3 categories. RESULTS: In the colorectal cancers, Cdx2 was expressed in 380 of 420 (90.5%) cases, and 349 of 380 (83%) cases showed strong and diffuse staining and 31 of 420 (7.5%) cases showed weakly positive staining. Forty patients (9.5%) of colorectal cancer were negative for Cdx2. All of the invasive breast cancers and all non-neoplastic control tissues except the regions of intestinal metaplasia in gastric mucosa, which showed strong Cdx2 expression, were negative for Cdx2. Loss of Cdx2 expression was observed more frequently in cases with deeper invasion (p<0.05), lymph node metastasis (p<0.05), poor histologic differentiation (p<0.001), and distant metastasis (p<0.05). CONCLUSIONS: Cdx2 could be a highly sensitive marker to detect metastasis from intestine and might be useful as a novel prognostic marker in colorectal cancers.