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Pleural effusion is a state of the presence of excess fluid in the pleural cavity, with 15% of cases associated with malignancy. This malignancy can be caused by adenocarcinoma, squamous cell carcinoma, small cell carcinoma, mesothelioma malignancy, and others. One way to do the examination is by immunohistochemical staining for example, TTF-1, calretinin, p40, CK5/6, p63. ΔNp63 (p40) is a biomarker types of basal/squamous accordance with nontransactivating isoforms of p63 gene. CK5/6 is keratin intermediate size, expressed in benign and malignant epidermal tumors, squamous mucosa, and myoepithelial. This study aims to prove the immunohistochemical examination of p40 and CK5 / 6 confirm the diagnosis of squamous cell carcinoma on cytology of pleural effusions with malignancy. This study was a descriptive observational cross-sectional design. 20 blocks pleural effusion cytology eligible performed immunohistochemical staining p40 and CK5 / 6. Positive expression characterized by stainning of nucleus and cytoplasm of cells suspected of being malignant. Expression is read by two specialists Pathology in blindly. A total of 20 samples were obtained the highest percentage of p40 expression in the whole sample is Squamous Cell Carcinoma ( 62.5%) and the highest expression of CK 5/6 also on Squamous Cell Carcinoma (40%). Immunocytochemistry p40 and CK 5/6 can be used to determine the malignancy of Squamous Cell Carcinoma on cytology samples of pleural effusions with malignancy.