Both mesotheliomas and renal cell carcinomas can present a wide variety of cytomorphologic features and histologic patterns. Because of this, renal cell carcinomas metastatic to the pleura and lung can be confused with mesotheliomas. Recently, a variety of positive carcinoma markers, including kidney-associated markers, have become available. The aim of this study is to investigate the value of some of these markers, specifically PAX8, PAX2, napsin A, carbonic anhydrase IX, and claudin-4, for assisting in distinguishing pleural epithelioid mesotheliomas from metastatic renal cell carcinomas. To do so, a total of 40 pleural epithelioid mesotheliomas and 55 renal cell carcinomas (33 clear cell, 10 papillary, and 12 chromophobe) were investigated. In all, 91% of the renal cell carcinomas expressed claudin-4, 89% PAX8, 60% PAX2, 71% carbonic anhydrase IX, and 29% napsin A. All of the mesotheliomas were positive for carbonic anhydrase IX and were negative for all of the other markers. On the basis of these results, it is concluded that claudin-4 and PAX8 have a higher sensitivity and specificity for assisting in discriminating between pleural epithelioid mesotheliomas and renal cell carcinomas when compared with all of the other positive carcinoma markers that are, at present, recommended to be included in the immunohistochemical panels used in this differential diagnosis. Even though PAX2 and napsin A are highly specific, because of their low sensitivity, they have only a limited value. Carbonic anhydrase IX is not useful.