CDX2 is a member of the caudal-related homeobox gene family that is expressed during the normal development of the intestinal tract. In addition to staining adenocarcinomas of the alimentary system, studies have demonstrated CDX2 positivity in a percentage of ovarian mucinous and endometrioid tumors, carcinoids, and some adenocarcinomas of other sites such as the urinary bladder, prostate, lung, and pancreas. However, CDX2 immunostaining in cervical adenocarcinomas has not been examined in detail with comparison to important clinicopathologic characteristics including histopathologic subtype, tumor stage, and patient follow-up. In this study of 81 invasive cervical adenocarcinomas, 24 of the cases (30%) demonstrated nuclear positivity. Ten of the 15 (67%) endometrioid tumors had positive nuclear staining, compared with 7 of the 33 (21%) endocervical "usual-type" carcinomas, and 7 of the 33 (21%) remaining subtypes (adenosquamous, glassy cell, clear cell, serous, villoglandular, enteric). The frequency of nuclear staining for the endometrioid subtype was significantly different compared with that for the endocervical and other subtypes (P=0.003). Some cases showed granular cytoplasmic staining with or without corresponding nuclear positivity. Positive nuclear or cytoplasmic staining for CDX2 did not correlate with disease stage or patient outcome. Our results indicate that cervical adenocarcinomas can show nuclear immunopositivity for CDX2 even in the absence of overt morphologic features of colorectal differentiation. The frequency and pattern of CDX2 staining in the more common histologic subtypes of cervical adenocarcinoma (endocervical usual-type and endometrioid) is parallel to that which is seen for adenocarcinomas of the upper gastrointestinal tract and pancreaticobiliary system.