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A large number of immunohistochemical markers that can facilitate the distinction between epithelioid pleural mesotheliomas and pulmonary peripheral adenocarcinomas have recently become available. The aim of this study is to compare the value of these new markers with others that are already commonly used for this purpose and to determine which are, at present, the best for discriminating between these malignancies. Sixty epithelioid mesotheliomas and 50 lung adenocarcinomas were investigated for expression of the following markers: calretinin, cytokeratin 5/6, WT1, thrombomodulin, mesothelin, CD44S, HBME-1, N-cadherin, E-cadherin, MOC-31, thyroid transcription factor-1 (TTF-1), BG-8 (Lewisy), carcinoembryonic antigen (CEA), Ber-EP4, B72.3 (TAG-72), leu-M1 (CD15), CA19-9, epithelial membrane antigen (EMA), and vimentin. All (100%) of the mesotheliomas reacted for calretinin, cytokeratin 5/6, and mesothelin, 93% for WT1, 93% for EMA, 85% for HBME-1, 77% for thrombomodulin; 73% for CD44S, 73% for N-cadherin, 55% for vimentin, 40% for E-cadherin, 18% for Ber-EP4, 8% for MOC-31, 7% for BG-8, and none for CEA, B72.3, leu-M1, TTF-1, or CA19-9. Of the adenocarcinomas, 100% were positive for MOC-31, Ber-EP4, and EMA, 96% for BG-8, 88% for CEA, 88% for E-cadherin, 84% for B72.3, 74% for TTF-1, 72% for leu-M1, 68% for HBME-1, 48% for CD44S, 48% for CA19-9, 38% for mesothelin, 38% for vimentin, 30% for N-cadherin, 14% for thrombomodulin, 8% for calretinin, 2% for cytokeratin 5/6, and none for WT1. After analyzing the results, it is concluded that calretinin, cytokeratin 5/6, and WT1 are the best positive markers for differentiating epithelioid malignant mesothelioma from pulmonary adenocarcinoma. The best discriminators among the antibodies considered to be negative markers for mesothelioma are CEA, MOC-31, Ber-EP4, BG-8, and B72.3. A panel of four markers (two positive and two negative) selected based upon availability and which ones yield good staining results in a given laboratory is recommended. Because of their specificity and sensitivity for mesotheliomas, the best combination appears to be calretinin and cytokeratin 5/6 (or WT1) for the positive markers and CEA and MOC-31 (or B72.3, Ber-EP4, or BG-8) for the negative markers. An extensive and detailed review of the literature is also provided.