One of the problems in studying serous effusion cytological samples is differentiation of reactive mesothelial cells from metastatic adenocarcinoma cells. In this study, the immunohistochemical diagnostic value of E-cadherin and desmin markers in differentiation of these 2 groups of cells was studied. Material and methods: Fifty cases of serous effusions were examined on Papanicolaou-stained and Diff quick-stained smears as well as Paraffin-embedded cell blocks. 30 cases were diagnosed as metastatic adenocarcinoma and 20 cases were diagnosed as reactive mesothelial hyperplasia with typical cytomorphologic features. All the cases were studied for E-cadherin and desmin immunoreactivity. Results: The all cases of metastatic adenocarcinoma reacted to E-cadherin and only 3 cases reacted to desmin, whereas among the 20 cases of reactive mesothelial cell hyperplasia, 18 cases stained with desmin and only one case was stained with E-cadherin. Considering the staining of the E-cadherin and desmin under conditions that the cells were stained with E-cadherin but not with desmin, sensitivity=90%, specificity=100%, positive predictive value (PPV)=100%, negative predictive value (NPV)=87% and accuracy=94% to identify metastatic adenocarcinoma. While under conditions that the cells were stained with desmin but not with E-cadherin, sensitivity=85%, specificity=100%, positive predictive value (PPV)=100%, negative predictive value (NPV)=90% and accuracy= 94% to identify reactive mesothelial cell hyperplasia. Conclusion: Employing this short panel can be helpful for better differentiation of adenocarcinoma and reactive mesothelial cells in serous effusions.