Most reports on antibodies that claimed to separate mesothelioma from pulmonary adenocarcinoma originated from academic centers or specialized immunohistochemistry laboratories, but little is known about how such stains perform in general practice laboratories. The Canadian Immunohistochemistry Quality Control program circulates tissue array slides to laboratories across Canada; these are stained and then interpreted by the local laboratory and by a set of experienced reviewers. For Canadian Immunohistochemistry Quality Control run 16, tissue array slides from 16 pulmonary adenocarcinomas and 6 mesotheliomas were stained in 36 different laboratories for CEA, CD15, CK5/6, and calretinin. A total of 736 results (cores) were interpretable. If 3 of 4 staining results concordant with the diagnosis was accepted as definitive, 166/192 (86.4%) mesothelioma cores and 461/544 (84.7%) adenocarcinoma cores were correctly diagnosed. However, if 4 of 4 concordant markers were required, then 93/192 (48.4%) mesothelioma cores and 265/544 (48.7%) adenocarcinoma cores were correctly diagnosed. Only 3/192 (1.6%) mesothelioma cores were incorrectly classified as carcinomas and 8/544 (1.5%) of adenocarcinoma cores incorrectly classified as mesotheliomas on the basis of the immunoprofile (ie, 3 of 4 or 4 of 4 marker results were discordant with the diagnosis). We conclude that, in a study based on results from nonspecialized laboratories, the combination of CEA, CD15, calretinin, and CK5/6, used as a panel, has a very low false-positive rate when separating pulmonary adenocarcinomas from mesotheliomas; however, single negative or incorrect results are common, therefore the panel is only useful diagnostically if 3 of 4 correct results are deemed acceptable for diagnosis.