Paraffin-embedded sections of various adenocarcinomas (13 colonic, 11 mucinous ovarian, 5 serous ovarian, 8 pancreatic, 6 ampullary, 12 gastric, 5 esophageal, 10 endometrial, 29 breast, and 55 lung) and 29 additional lung carcinomas (nonadenocarcinomas) were immunostained with antibodies to CDX2 protein, cytokeratin 7 (CK7), and cytokeratin 20 (CK20). The 84 lung carcinomas were also stained with antibody to thyroid transcription factor-1 (TTF-1). All colorectal and most ovarian mucinous carcinomas were strongly and diffusely immunoreactive for CDX2. Esophageal, gastric, and ampullary adenocarcinomas showed variable immunoreactivity for CDX2. All breast, nonmucinous ovarian, and most endometrial and pancreatic adenocarcinomas showed no immunoreactivity for CDX2. CK7 and CK20 expression was similar to previous reports. Ten of 84 primary lung carcinomas (12%) were immunoreactive for CDX2 expression. Of these, 5 (4 adenocarcinomas and 1 large cell carcinoma) were reactive for TTF-1. Gene expression profiling data--available for 32 of these 84 tumors--showed CDX2 gene expression in 7 of 8 (88%) CDX2 immunoreactive tumors whereas only 1 of 24 (4%) tumors negative for CDX2 immunoreactivity showed CDX2 gene expression. The authors conclude that CDX2 is a relatively specific marker for tumors with intestinal differentiation, with the caveat that its expression can be seen in primary large cell and adenocarcinomas of the lung and mucinous carcinomas of the ovary.