The authors investigated the expression of keratin, carcinoembryonic antigen (CEA), and an epithelial marker derived from milk fat globule membranes in 12 mesotheliomas and 100 diverse adenocarcinomas with immunohistochemical methods. The authors employed a monoclonal antibody to keratin designated as AE1, as well as the following commercially available antisera: rabbit anti-whole human keratin, rabbit anti-CEA. and a monoclonal antibody to an epithelial factor designated as MFG-2. Expression of keratin was found in all the mesotheliomas and adenocarcinomas with antibody AEl as well as with the rabbit antiserum; CEA was detectable in 65% of the adenocarcinomas but two mesotheliomas also reacted weakly. With antibody MFG-2, positive results were obtained in 85% of the adenocarcinomas and in none of the mesotheliomas. All of 64 (100%) breast-, lung-and ovary-derived adenocarcinomas immunostained positively with antibody MFG-2. This is of particular significance because pulmonary and ovarian adenocarcinoma frequently may be indistinguishable clinically and histologically from epithelial mesothelioma. The authors conclude that antikeratin antibodies are not useful in the distinction of adenocarcinoma from mesothelioma. Because of its greater sensitivity and specificity, MFG-2 is superior to CEA in this differential diagnosis.