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 EMA and desmin are used in order to differentiate between reactive and malignant mesothelial proliferation. Patients & Methods: This prospective study includes 13 cases of MM, 6 cases of atypical mesothelial proliferations, and 17 cases of reactive mesothelial proliferations. Cases were collected from Chest Department of Faculty of Medicine, Benha University and International Medical Center (IMC), in the period 2012-2014. EMA and desmin 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%, 7.7% of reactive mesothelial lesions, atypical mesothelial lesions and MM respectively. EMA was positive in all cases (100%) of atypical mesothelial lesions and in 92.3% of MM cases but in 5.9% of reactive mesothelial lesions (p < 0.01). The calculated mean SMRP was 6.6 nM. SMRP levels were higher than the calculated mean value in 76.9% and 66.7% of MM and atypical mesothelial reaction respectively and in 17.6% of studied reactive mesothelial lesions, which was statistically highly significant correlation (p < 0.01). Conclusion: Combined estimation of SRMP level and immunohistochemical detection of both EMA and desmin is useful tool for differentiation between reactive mesothelial hyperplasia and malignant mesothelioma.