Only recently have immunohistochemical markers been recognized that are commonly expressed in epithelial mesotheliomas but not in adenocarcinomas. Among these, calretinin generated a great deal of interest, but the number of studies evaluating the practical use of calretinin immunostaining in the diagnosis of mesothelioma is limited, and the study results are controversial. To evaluate whether calretinin immunostaining can assist in distinguishing between epithelial pleural mesothelioma and lung adenocarcinoma and other carcinomas metastatic to the pleura, 38 pulmonary adenocarcinomas, 117 nonpulmonary adenocarcinomas, 28 squamous cell carcinomas of the lung, 8 large-cell undifferentiated carcinomas of the lung, and 9 transitional cell carcinomas metastatic to the lung were studied. Reactivity was observed in all of the 38 mesotheliomas, whereas only 3 of the 38 pulmonary adenocarcinomas and 11 of the 117 nonpulmonary adenocarcinomas (5/38 ovarian, 2/15 endometrial, 2/23 breast, 2/16 colonic, 0/8 kidney, 0/8 prostatic, 0/6 thyroid, and 0/3 pancreatic) exhibited weak or focal staining. Eleven of the 28 squamous carcinomas of the lung were also positive. No reactivity was observed in any of the large cell undifferentiated carcinomas of the lung or in the transitional cell carcinomas. It is concluded that calretinin immunostaining is not only helpful in discriminating epithelial pleural mesotheliomas from pulmonary adenocarcinomas but that it can also assist in distinguishing epithelial mesotheliomas from nonpulmonary adenocarcinomas metastatic to the pleura.