Background: Malignant pleural mesothelioma (MPM) and non-small cell lung carcinoma (NSCLC) are common diseases with rising incidence, patients have different prognosis and are treated differently, and thus it is very important to diagnose these malignancies properly. This differential diagnosis is not easy. The aim of this work is to evaluate the role of BRCA-associated protein (BAP1) and calretinin in the differentiation between mesothelioma and non-small cell lung carcinoma. Methods:BRCA-associated protein (BAP1) and calretinin were assessed by immunohistochemistry in 44 lung paraffin blocks, malignant pleural mesothelioma (22 cases) and non-small cell lung cancer (22 cases). Results: BAP1 expression was observed in 20/22(90.9%) of cases of non small cell lung carcinoma, while only 8/22 (36.4%) of malignant pleural mesothelioma showed positive BAP1 immunoreactivity. There was a statistically significant difference in BAP1 expression between non-small lung carcinoma and malignant pleural mesothelioma (p value = 0.001). Calretinin expression was observed only in 3/22 (13.6%) of cases of non-small cell lung carcinoma, while 18/22 (81.8%) of malignant pleural mesothelioma showed positive calretinin immunoreactivity. There was a statistically significant difference in calretinin expression between non-small lung carcinoma and malignant pleural mesothelioma (p value< 0.001). BAP1 has sensitivity of 90.9%, specificity of 63.6%, predictive value positive (PVP) of 71.4% and predictive value negative (PVN) of 87.5%. Calretinin has sensitivity of 81.8%, specificity of 86.4%, PVP of 85.7% and PVN of 82.6%. Conclusion: BAP1 and calretinin IHCcan be used with other immunohistochemistry panel to differentiate between malignant pleural mesothelioma and non-small lung carcinoma.