Several immunohistochemical markers, among them calretinin, thrombomodulin (CD141), keratin 5, and mesothelin, have been documented or suggested as useful markers for positive identification of mesothelioma and to differentiate it from pulmonary adenocarcinoma; numerous studies have documented their variable specificity. However, expression of these markers in other types of lung carcinomas has not been systematically explored, although these tumors can enter in the differential diagnosis of mesothelioma. In this study we immunohistochemically evaluated 596 lung carcinomas of different types for the four above-mentioned mesothelioma markers, all of which reacted with a great majority of epithelioid mesotheliomas studied for comparison. Calretinin expression was common in giant cell carcinomas (67%), small cell carcinomas (49%), and large cell carcinomas (38%), whereas it was rare in usual adenocarcinomas but slightly more common in those with neuroendocrine differentiation (11% and 17%, respectively). Thrombomodulin was present in all keratinizing squamous carcinomas and the great majority (87%) of nonkeratinizing tumors in a membrane-staining pattern. It was moderately common in small cell (27%) and large cell carcinomas (25%) but relatively rare in adenocarcinomas (13%). Keratin 5 was expressed in all keratinizing and the great majority (87%) of nonkeratinizing squamous carcinomas, and a majority of large cell carcinomas (56%) and some small cell carcinomas (27%). It was rare in acinar adenocarcinomas (12%) and absent in those with neuroendocrine differentiation. Mesothelin was present in more than half (53%) of adenocarcinomas and a minority (13%) of large cell carcinomas but was absent in small cell carcinomas. In squamous carcinomas it was more often seen in nonkeratinizing versus keratinizing tumors (31% vs 16%). These results show that each of these "mesothelioma" markers reacts with different subsets of pulmonary carcinomas with a variable frequency; this should be considered when using these markers in the differential diagnosis of thoracic tumors.