Background: Lung cancer is the second most common cancer, and the leading cause of cancer mortality. Malignant pleural mesothelioma is a highly aggressive malignant neoplasm, and epithelioid mesothelioma is the commonest histological subtype. MUC4 is a high-molecular weight glycoprotein that encoded by MUC4 gene. Aim: The aim of this study was to evaluate MUC4 expression in LAC, LSqCC, and PEM. Materials and Methods: This retrospective study was done upon 70 different lung and pleural lesions designated as; 30 cases of LAC, 20 cases of LSqCC and 20 cases of PEM. MUC4 immunostaining was done and assessed for each case. Results: There is high significant statistical correlation between MUC4 expression with LAC, LSqCC, and PEM cases (P value=0.0001). 90% and 95% of LAC and LSqCC respectively are positive. All PEM cases are negative. The sensitivity and specificity of MUC4 in differentiating PEM from lung cancer including LAC and LSqCC are 92% and 100% respectively. Significant statistical correlation is found between MUC4 and histological subtype (P value > 0.05), grade (P < 0.01), and TNM stage (P < 0.05) of LAC. Significant statistical inverse correlation is found between MUC4 expression and grade of LSqCC (P value> 0.05). Conclusions: MUC4 IHC can differentiate PEM from LAC and LSqCC. MUC4 expression increases with aggressive LAC, and increases with well-differentiated LSqCC.