A panel of seven monoclonal antibodies including anti-vimentin, anti-keratin markers AE1/AE3 and EAB902, human milk fat globule (HMFG-2), B72.3, anti-carcinoembryonic antigen (CEA), and anti-Leu-M1 were used for an immunoperoxidase staining assay to determine their value in the differentiation of pleural mesothelioma from lung adenocarcinoma. Anti-vimentin positively identified 86% of the mesotheliomas and none of the adenocarcinomas. AE1/AE3, EAB902, and B72.3 reacted with a high percentage of both mesothelioma and adenocarcinoma specimens. With HMFG-2, both membrane and cytoplasmic staining was observed in 92% of the adenocarcinomas and in 14% of the mesotheliomas, whereas 26% of the mesotheliomas only exhibited membrane staining. Eighty percent of the adenocarcinomas and 8% of the mesothelioma tissues stained with anti-Leu-M1. Anti-CEA did not react with any of the 50 mesotheliomas tested but did react with 95% of the lung adenocarcinomas tested. From this study, it was concluded that anti-CEA and anti-Leu-M1 were the most effective of the seven tumor markers evaluated; and that 100% of the pleural mesothelioma tissues could be correctly differentiated from lung adenocarcinomas using a panel consisting of anti-vimentin, HMFG-2, anti-CEA and anti-Leu-M1 monoclonal antibodies.