Needle aspiration specimens from 74 cases of hepatocellular carcinoma (HCC) diagnosed between January 1986 and December 1992 were reviewed and compared with 57 other lesions. The most specific cytologic findings for HCC included capillaries separating tumor cells (34%), bile associated with malignant cells (19%), and endothelial cells lining clusters of neoplastic cells (18%). Less specific findings included polygonal cells with central nuclei resembling normal hepatocytes and intranuclear inclusions. Tissue core fragments available in 53 cases of HCC disclosed that a weak keratin (AE1/AE3) stain (75% of HCC), a canalicular pattern of polyclonal carcinoembryonic antigen (54%), and a positive alpha-fetoprotein stain (58%) are diagnostic of HCC. All HCCs were negative for monoclonal carcinoembryonic antigen. In situ hybridization for albumin mRNA was positive in 27 of 33 cases of HCC. The diagnosis of HCC by needle biopsy should include cytologic findings and the appropriate immunohistochemical profile, along with detection of albumin mRNA by in situ hybridization.