To distinguish carcinoma, either adenocarcinoma (ADC) or squamous cell carcinoma (SCC), and malignant mesothelioma (MM) in effusion can be a diagnostic challenge based on morphology alone. This study evaluates the utility of WT-1, p63, MOC31, mesothelin, and cytokeratin (K903 and CK5/6) immunostains in effusions when ADC and SCC of the lung are in the differential diagnosis with MM. A cohort of 43 effusions consisting of lung ADC (N = 10), SCC (N = 15), and MM (N = 18, mostly (16) pleural based), was subjected to immunostains using the above mentioned antibodies. WT-1 was positive in 100% MM, 0% ADC, and 0% SCC cases while p63 was positive in 0% MM, 30% ADC, and 80% SCC cases. Stain for MOC31 was positive in 100% ADC, 67% SCC, and 35% MM cases. Similarly, mesothelin antibody stained 100% ADC, 60% SCC, and 47% MM cases. Antibodies for K903 and CK5/6 stained 100% SCC cases but fewer ADC cases (40 and 10%, respectively). In conclusion, in this cohort of mostly pleural malignant effusion, MM can be identified with positive staining for WT-1 and negative staining for p63. Conversely, negative staining with WT-1 and positive staining for p63 exclude MM. Used as part of an immunostain panel, cytokeratin markers (CK5/6 and K903) are useful in differentiating SCC from ADC when MM is already excluded, and MOC31 might have limited value in differentiating ADC from MM. A negative stain with MOC31 can exclude lung ADC. Mesothelin, on the other hand, is not useful in the differential diagnosis of ADC, SCC, and MM.