To investigate the value of different tissue markers in the histologic diagnosis of hepatic tumors, we performed immunoperoxidase stains for alpha-fetoprotein (AFP), alpha-1-antitrypsin (AAT), carcinoembryonic antigen (CEA), and an erythropoiesis-associated antigen (ERY-1) on formalin-fixed, paraffin-embedded samples from 107 primary and metastatic tumors of the liver. AFP was present in 17% of the hepatocellular carcinomas, in 7% of the metastatic carcinomas, and in none of the cholangiocarcinomas. AAT was present in 41% of the hepatocellular carcinomas, in 37% of the cholangiocarcinomas, and in 50% to 70% of the metastatic carcinomas of the liver. Intracytoplasmic CEA was found in 75% of the cholangiocarcinomas, in 92% to 100% of the metastatic carcinomas, and in only one of the mixed hepatocellular-cholangiocarcinomas. ERY-1 was present in 89% of the hepatocellular carcinomas, whereas none of the cholangiocarcinomas or metastatic carcinomas stained for this marker. We conclude that immunohistochemical assays for AFP and AAT are of limited value in the differential diagnosis of hepatic tumors. However, immunohistochemical stains for ERY-1 and CEA can be valuable in differentiating hepatocellular carcinomas from metastatic tumors.