Background: Malignant mesothelioma can be difficult to be distinguished from lung adenocarcinoma without immunohistochemistry. However, conventional mesothelial markers until now have not the optimal sensitivity and specificity necessitating identification of new markers. Methods: SOX6 and HEG1were evaluated by immunohistochemistry in 55 cases of epitheloid mesothelioma and 50 cases of lung adenocarcinoma. All cases were previously immunostained by calretinin and D2-40. both sensitivity and specificity for distinguishing epithelioid mesothelioma from adenocarcinoma were calculated. Results: SOX6 expression was present in 54 of 55 (98%) cases of epithelioid mesothelioma, compared with its expression in only 4 of 50 (8%) cases of lung adenocarcinoma. The sensitivity and specificity of SOX6 expression for differentiating epithelioid mesothelioma from lung adenocarcinoma were 98.2% & 92.0% respectively. HEG1 expression was present in 52 of 55 (94.5%) cases of epithelioid mesothelioma, compared with its complete negative expression in all studied cases of lung adenocarcinoma. The sensitivity and specificity of HEG1 for differentiation epithelioid mesothelioma from lung adenocarcinoma were (94.5%& 100% respectively). The sensitivity and specificity of both SOX6 and HEG1were higher than those of calretinin and D2-40 Conclusion: SOX6 and HEG1 may be used as immunohistochemical markers for differentiating epithelioid mesothelioma from lung adenocarcinoma.