Background: The role of combinations of tumor markers such as carcinoembryonic antigen (CEA), carbohydrate antigens (CA) 125, 15-3, and 19-9, and CYFRA 21-1 (a fragment of cytokeratin 19) in diagnosing malignant pleural effusion (MPE) has not been clearly established. Objectives: This meta-analysis was performed to establish the overall diagnostic accuracies of combinations of these pleural fluid tumor markers for MPE. Methods: The PubMed, Ovid, Embase, Web of Science, and Cochrane bibliographic databases were searched. Sensitivity, specificity, and other measures of the accuracy of combinations of pleural CEA, CA 125, CA 15-3, CA 19-9, and CYFRA 21-1 in the diagnosis of MPE were pooled after a systematic review of English-language studies. Results: Twenty studies met the inclusion criteria. For pleural fluid tumor marker combinations including more than 3 studies, the summary estimates of the sensitivity/specificity for diagnosing MPE were as follows: CEA + CA 125, 0.65/0.98; CEA + CA 15-3, 0.64/0.98; CEA + CA 19-9, 0.58/0.98; CEA + CYFRA 21-1, 0.82/0.92; and CA 15-3 + CYFRA 21-1, 0.88/0.94. Conclusions: In patients with undiagnosed pleural effusion, the combinations of positive pleural CEA + CA 15-3 and CEA + CA 19-9 are highly suspicious for pleural malignancy, but the sensitivity of these tests is poor. Therefore, their routine role in the diagnostic algorithm of these patients is questionable, and management decisions should depend on positive cytological or biopsy results from the pleura.