Hepatobiliary and pancreatic mucinous cystadenocarcinomas with mesenchymal stroma are relatively rare neoplasms that occur preponderantly in women, suggesting a role for unidentified sex-specific factor(s) in the pathogenesis of these tumors. We used paraffin tissue immunohistochemical analysis with an appropriate panel of monoclonal antibodies to look for estrogen and progesterone receptors in two cases of hepatobiliary mucinous cystadenocarcinoma with mesenchymal stroma and one case of pancreatic mucinous cystadenocarcinoma. In all three of these cases, the nuclei of tumor stroma and, in the hepatic tumors, the nuclei of tumor epithelium, reacted with both antibodies. These data strongly suggest that a relationship to hormonal functions exists for these tumors. Because of the rarity of these tumors we also investigated the expression of a variety of oncoprotein antigens, epithelial antigens, and cytoskeletal antigens. The oncoprotein antigens, p53 and c-erbB-2, were focally expressed in hepatic and pancreatic tumor epithelium; bcl-2 was focally expressed in hepatic tumor epithelium. Keratin was strongly expressed in most epithelial cells. In addition, epithelial membrane antigen, carcinoembryonic antigen, and chromogranin were focally expressed in epithelial cells. Actin and vimentin were strongly expressed in most stromal cells but not in epithelial cells, and desmin expression was similar but less widespread.