A panel of antibodies to intermediate filaments, oncofetal antigens, and hepatocellular markers was tested on a prospective series of liver fine-needle aspirates to determine its utility in distinguishing hepatocellular carcinoma (HCC) from metastatic carcinomas. All fine-needle aspirations were assisted to ensure adequate cellularity, and were examined by a multimodal approach that included the preparation of B-5-formaldehyde-fixed cell blocks by the plasmathrombin technique. alpha-Fetoprotein was positive in four of eight HCCs, including the one example of combined hepatocellular-cholangiocarcinoma, but negative in the one case of pure cholangiocarcinoma and all cases of metastatic carcinoma. Carcinoembryonic antigen positivity was noted in four HCCs, a high proportion of metastatic adenocarcinomas, and occasional metastatic squamous cell carcinomas, but not in the one example of cholangiocarcinoma. Hepatitis B surface antigen was positive in only two cases of HCCs, but not in any metastatic tumors. Keratin and vimentin were positive, respectively, in four and three HCCs, and a variable proportion of metastatic carcinomas often coexpressed both antigens. Epithelial membrane antigen was positive in five of the eight HCCs. Our findings are consistent with the view that alpha-fetoprotein and hepatitis B surface antigen are reliable markers for HCC. However, none of the immunocytochemical markers reliably distinguished the primary site of metastatic carcinoma. The intensity of the immunostains in the fine-needle aspirations was comparable with that observed in tissues, but fragmentation of cell groups interfered with interpretation. Multiple passes and verification of the cellularity of the aspirates are crucial factors for the success of this approach to diagnosis.