To evaluate the consistency of cytoplasmic immunoreactivity in hepatocellular carcinoma (HCC), we performed immunohistochemical stains for 4 commercial anti-thyroid transcription factor (TTF)-1 antibodies (DAKO, Zymed, Novocastra, Santa Cruz Biotechnology [see text]) on 77 HCCs and 334 nonhepatic epithelial tumors. The HCC cases were submitted for hepatocvte antigen immunohistochemical stain. Heat-induced epitope retrieval (HIER) methods were used: with DAKO Target Retrieval Solution, the positive rates of cytoplasmic TTF-1 in HCC for DAKO, Zymed, Santa Cruz, and Novocastra antibodies were 58% (45), 14% (11), 6% (5), and 0% (0), respectively; with EDTA buffer, the positive rates increased to 70% (54), 40% (31), 69% (53), and 0% (0), respectively. Immunoreactivity for the DAKO anti-TTF-1 antibody generally correlated with that for hepatocyte antigen. Among nonhepatic tumors, 2 of 6 ovarian mucinous carcinomas and 2 of 11 pancreatic adenocarcinomas showed cytoplasmic reactivity for the DAKO antibody; 28 cases showed nonspecific cytoplasmic staining for the Santa Cruz antibody with EDTA HIER. Zymed and Novocastra antibodies did not produce cytoplasmic staining in nonhepatic tumors. Owing to the staining variation, we do not consider TTF-1 a reliable marker to distinguish HCC. In general, the Novocastra antibody with EDTA HIER is superior for its consistent nuclear positivity and absence of erratic cytoplasmic staining.