Cdx2 has been identified as a marker of colon cancer in RNA-profiling experiments. We show here that the detection of Cdx2 protein by immunohistochemistry correlates well with RNA transcript levels as detected by oligonucleotide microarrays. Using tissue microarrays containing most normal tissue types and an antibody to the Cdx2 protein, strong diffuse Cdx2 staining was only seen in the nuclei of small and large intestinal epithelium and portions of the pancreatic duct system. In tissue microarrays containing 745 cancers from many anatomic sites, colonic adenocarcinomas showed strong extensive staining in 90% of cases, with adenocarcinomas of the stomach, esophagus, and ovary (endometrioid and mucinous types) showing extensive staining in only 20-30% of cases. Other types of carcinomas showed extensive staining in only </=1% of cases. Of 30 neuroendocrine tumors examined, carcinoids of the midgut and hindgut had the most cases with extensive staining (73% and 44%, respectively), thus paralleling the distribution of Cdx2 expression in adenocarcinomas. Cdx2 shows a limited range of expression in the spectrum of human tissues and neoplasia and thus may have utility in determining the site of origin of tumors in certain clinical situations.