Background: Malignant mesothelioma (MM) carries a poor prognosis and response rates to palliative chemotherapy remain low. The diagnosis of malignant mesothelioma is frequently difficult, the most common differential diagnosis being reactive pleural conditions and metastatic adenocarcinoma. Several studies have used immunohistochemical markers to distinguish between reactive and neoplastic mesothelial cells. Soluble mesothelin levels in serum have recently been shown to be highly specific and moderately sensitive for mesothelioma. A combined detection of serum levels of mesothelin and immunohistochemical expression of desmin and EMA are used in order to differentiate between reactive mesothelial proliferations, and malignant mesothelioma of epithelioid type. Patients and methods: This prospective study includes 17 cases of reactive mesothelial proliferations, 6 cases of atypical mesothelial proliferations and 13 cases of MM. Cases were collected from the Chest Department, Faculty of Medicine, Benha University and International Medical Center (IMC), in the period 2012–2014. Desmin and epithelial membrane antigen (EMA) immunohistochemical staining were performed in all cases and the pattern of expression was analyzed. Soluble mesothelin related peptide (SMRP) was estimated for all cases. Results: Desmin expression was positive in 88.2%, 0%, and 7.7% of reactive mesothelial proliferations, atypical mesothelial proliferations and MM respectively. EMA was positive in 5.9% of reactive mesothelial proliferation, 100% of atypical mesothelial proliferations and 92.3% of MM cases (P