Determination of the cause of malignant pleural effusions is important for treatment and management,especially in cases of unknown primaries. There are limited biomarkers available for prediction of the cause ofmalignant pleural effusion in clinical practice. Hence, we evaluated pleural levels of five tumor biomarkers (CEA,AFP, CA125, CA153 and CA199) in predicting the cause of malignant pleural effusion in a retrospective study.Kruskal-Wallis or Mann-Whitney U tests were carried out to compare levels of tumor markers in pleural effusionamong different forms of neoplasia - lung squamous cell carcinoma, adenocarcinoma, or small cell carcinoma,mesothelioma, breast cancer, lymphoma/leukemia and miscellaneous. Receiver operator characteristic analysiswas performed to evaluate sensitivity and specificity of biomarkers. The Kruskal-Wallis test showed significantdifferences in levels of pleural effusion CEA (P<0.01), AFP (P<0.01), CA153 (P<0.01) and CA199 (P<0.01), butnot CA125 (P>0.05), among the seven groups. Receiver operator characteristic analysis showed that, comparedwith other four tumor markers, CA153 was the best biomarker in diagnosing malignant pleural effusions of lungadenocarcinoma (area under curve (AUC): 0.838 (95%confidence interval: 0.787, 0.888); cut-off value: 10.2U/ml; sensitivity: 73.2% (64.4-80.8)%, specificity: 85.2% (77.8-90.8)%), lung squamous cell carcinoma (AUC:0.716 (0.652, 0.780); cut-off value: 14.2U/ml; sensitivity: 57.6% (50.7-64.3)%, specificity: 91.2% (76.3-98.0)%),and small-cell lung cancer (AUC: 0.812 (0.740, 0.884); cut-off value: 9.7U/ml; sensitivity: 61.5% (55.0-67.8)%,specificity: 94.1% (71.2-99.0)%); CEA was the best biomarker in diagnosing MPEs of mesothelioma (AUC:0.726 (0.593, 0.858); cut-off value: 1.43ng/ml; sensitivity: 83.7% (78.3-88.2)%, specificity: 61.1% (35.8-82.6)%)and lymphoma/leukemia (AUC: 0.923 (0.872, 0.974); cut-off value: 1.71ng/ml; sensitivity: 82.8% (77.4-87.3)%,specificity: 92.3% (63.9-98.7)%). Thus CA153 and CEA appear to be good biomarkers in diagnosing differentcauses of malignant pleural effusion. Our findings implied that the two tumor markers may improve the diagnosisand treatment for effusions of unknown primaries.