Cancers share many similarities in growth patterns, cellular morphology, and oncofetal antigen expression with embryonic tissue. To better understand the mechanisms underlying malignant transformation and its relationship to developmental processes, we studied the expression of Cdx-2, an intestinal epithelium-specific homeodomain protein, in colorectal adenoma and carcinoma. By immunohistochemistry with a polyclonal Cdx-2 antibody we have shown that Cdx-2 expression is markedly reduced in the later stages of human colorectal carcinogenesis, namely, high grade dysplasia and invasive carcinoma. The same findings occur in 1,2-dimethylhydrazine-induced rat colorectal tumors, confirming the parallels between the rat model and the human disease. As homeodomain proteins play major roles in directing the regionalization of body parts and in organogenesis and cellular phenotypic specification, a reduction of Cdx-2 expression in the late stages of colorectal carcinogenesis may reflect a concomitant deviation of the neoplastic tissue from the normal intestinal epithelial phenotype.