Chordoma is one of several similar appearing neoplasms in the retroperitoneum, pelvis, and abdomen with a combination of features including clear cells, with or without cytoplasmic vacuoles, papillary profiles, and a myxoid or myxohyaline stroma. The differential diagnosis of a cellular myxoid or mucinous tumor in a small biopsy, when the entire tumor is not available for pathologic examination, includes metastatic mucinous adenocarcinoma of colorectal and other similar-appearing neoplasms, renal cell carcinoma, and myxopapillary ependymoma. We compared immunohistochemical reactivity of 18 chordomas with 20 colonic adenocarcinomas, 20 renal cell carcinomas, and six myxopapillary ependymomas using antibodies to vimentin, cytokeratin, epithelial membrane antigen, S100 protein, Leu 7, glial fibrillary acidic protein, and carcinoembryonic antigen. All chordomas were immunoreactive for vimentin and cytokeratin, 83% for epithelial membrane antigen, and 83% for S100 protein. Myxopapillary ependymomas were distinguished by immunoreactivity for vimentin and glial fibrillary acidic protein in all cases and S100 protein in 50%. All colonic adenocarcinomas were positive for cytokeratin, epithelial membrane antigen, and carcinoembryonic antigen. Renal cell carcinomas were uniformly reactive for epithelial membrane antigen and cytokeratin, nonreactive for carcinoembryonic antigen, and variably reactive for S100 protein (5%) and vimentin (25%). These data indicate that a panel of immunohistochemical markers can be useful in distinguishing chordoma from potential histologic mimics.