CDX2 is a caudal-related homeobox transcription factor whose expression in the adult is normally restricted to the intestinal epithelium; it is implicated in the development and maintenance of the intestinal mucosa. The specific aim of this study was to elucidate the potential etiological role of CDX2 protein in colorectal carcinogenesis. We have analyzed the expression pattern of CDX2 protein in relation to the phenotype of 123 sporadic colorectal cancers by immunohistochemistry using tissue microarray. Strong CDX2 immunostaining was seen in the nuclei of corresponding normal intestinal epithelium. Interestingly, loss of CDX2 immunostaining was observed in 29 (23.6%) of 123 colorectal adenocarcinomas and its expression was correlated with the differentiation grade of the carcinoma (Chi-Square test, p<0.01). Clinically, CDX2 protein was immunopositive in 11 (91.7%) of 12 cases corresponding to stage A, 40 (85.1%) of 47 corresponding to stage B, 39 (69.6%) of 56 corresponding to stage C, and 4 (50.0%) of 8 corresponding to stage D. Statistically, CDX2 protein expression was related to tumor stage (Bartholomew test, p<0.05) and lymph node metastasis (Chi-Square test, p<0.05). These results indicate that loss of expression of CDX2 protein may play an important role in the tumorigenesis of colorectal cancers and that CDX2 expression represents a highly significant marker, which is able to identify a subset of patients at high risk.