Immunohistochemistry occasionally is used to determine the lineage of entirely necrotic tumors. However, the sensitivity and specificity of antibodies on necrotic tissue are unknown. To determine the usefulness of immunohistochemistry with necrotic lesions, a series of 24 known tumors consisting of 14 carcinomas, 2 lymphomas, 2 melanomas, and 6 sarcomas (all with extensive necrosis) was examined for reactivity with 6 cytokeratin antibodies, S100, and LCA. Carcinomas stained positively with at least 1 cytokeratin antibody in 78% of the cases. The cytokeratin antibodies with the highest sensitivity were AE1, AE1/3, S903, and PANCK. These antibodies also retained specificity for epithelial differentiation; no reactivity was observed in the 10 necrotic nonepithelial tumors. LCA retained its reactivity with necrotic lymphoma, but S100 reacted with only one third of the necrotic lesions. Unexpectedly, reactivity for LCA and S100 occurred in some necrotic carcinomas. Keratin markers can be used on necrotic tissue to determine epithelial differentiation, but the results obtained with S100 and LCA on necrotic tissue should be interpreted with caution.