CDX2 is a homeobox domain-containing transcription factor that is important in the development and differentiation of the intestine. In this study, we examined CDX2 expression in normal and neoplastic human colon using a newly isolated monoclonal antibody. When compared to the intensity observed in adjacent normal mucosal epithelial cells, strong nuclear staining for CDX2 was observed in 10 (100%) of 10 colonic adenomas, 30 (88.2%) of 34 colorectal adenocarcinomas, including 17(94.47%) of 18 well-or moderately differentiated tumors and 13(81.2%) of 16 high-grade tumors. The percentage of CDX2 immunopositive cells was generally lower in carcinomas than in adenomas (p<0.001) and lower in moderately or poorly differentiated tumors than in well-differentiated tumors (p<0.001). There was an inverse correlation between CDX2 expression and tumor grade, tumor stage and lymph node metastasis (respectively, p<0.001; p<0.05; p<0.001), but this was not associated with age, gender, or tumor location and size. These results indicate that loss of expression of CDX2 protein may play an important role in the tumorigenesis of colorectal cancers. Down-regulation of CDX2 may cause dedifferentiation of gastrointestinal epithelial cells.