Combined hepatocellular-cholangiocarcinoma is a rare form of primary liver cancer showing features of both hepatocellular and biliary epithelial differentiation. In a review of 24 cases of this tumor, three histologic types were encountered. Four cases were Type I or "collision tumors," apparently a coincidental occurrence of both hepatocellular carcinoma and cholangiocarcinoma in the same patient. Twelve cases were Type II or "transitional tumors," in which there were areas of intermediate differentiation and an identifiable transition between hepatocellular carcinoma and cholangiocarcinoma. Eight cases were Type III or "fibrolamellar tumors" which resembled the fibrolamellar variant of hepatocellular carcinoma but which also contained mucin-producing pseudoglands. Type III tumors differ from other combined tumors, occurring at a younger age, in the absence of cirrhosis, and having a slightly longer survival. Immunohistochemical (immunoperoxidase) staining for intracellular antigens showed that alpha-fetoprotein is a fairly specific, although insensitive, marker of hepatocellular differentiation in primary liver cancers, being present in 50% of typical hepatocellular carcinomas and in hepatocellular areas in 29% of combined tumors, but in no cholangiocarcinomas or cholangiocellular areas of combined tumors. Keratin is a good marker of biliary epithelial differentiation, being found in 90% of cholangiocarcinomas and in 52% of combined hepatocellular cholangiocarcinomas, but in no hepatocellular carcinomas. Alpha-1-antitrypsin, fibrinogen, IgG, and carcinoembryonic antigen may be found in both hepatocellular carcinoma, cholangiocarcinoma, and in combined tumors; these antigens are therefore of limited use in differential diagnosis.