It is difficult to distinguish epithelial malignant tumors in the pleura. The purpose of this paper is to explore the role of immunohistochemistry in distinguishing malignant mesothelioma from lung adenocarcinoma in the pleura. S-P immunohistochemical method was used to detect expression of vimentin, mesothelial cell (MC), calretinin (CR), thyroid transcription factor-1 (TTF-1), carcino-embryonic antigen (CEA), surfactant protein-B (Sp-B) and cytokeratin (CK) in 56 cases of epithelial malignant tumors in the pleura. In 56 cases of epithelial malignant tumors in the pleura, 24 cases of malignant mesothelioma and 22 cases of lung adenocarcinoma were ascertained, the source of 8 cases of metastatic adenocarcinoma was not known and the other 2 cases of tumor were difficult to be distinguished. The expression of vimentin, MC, CR, TTF-1, CEA, Sp-B between mesothelioma and adenocarcinoma was significantly different (P < 0.001 or P < 0.002) (t value was 4.90, 4.85, 3.50, 9.03, 8.58, 3.49 respectively). CK positive expression was seen in all 13 cases of malignant mesothelioma and 5 cases of lung adenocarcinoma. Vimentin, MC, CR, TTF-1, CEA, Sp-B are ideal markers in distinguishing malignant mesothelioma from lung adenocarcinoma in the pleura by using immunohistochemical method.