Aim: Pleural effusion is a common diagnostic problem. Tumor marker levels in pleural effusion may be help to distinguish pleural malignancy, but the precise diagnostic value of these markers remains unclear. The aim of this study was to investigate the diagnostic value of CEA, CA15-3, CA 19-9 and CA-125. Methods: Pleural fluid and serum levels of these markers were assayed prospectively in 89 patients with pleural effusion (35 malignant and 54 benign) and 25 healthy individuals. The patients were separated as benign or malignant. Results: All pleural and serum tumor markers levels were statistically higher in malignant group than in the benign and control groups. CEA was the marker which had the highest sensitivity (41.6%), specificity (100%) and accuracy (74.1%). CA 15-3 had also similar sensitivity, specificity and accuracy (38.8%, 100% and 73.0%, respectively). CA 19-9 and CA 125 sensitivity, specificity and accuracies were lower. CEA+CA 15-3+ CA-125 combination elevated the diagnostic value to 100% specificity and 78.3% accuracy. The highest diagnostic value was observed in CA 15-3+CA-125 combination (100% specificity and 80.9% accuracy). Moreover, pleural CEA and CA 15-3 levels were significantly higher in patients with primary lung cancer compared to those of patents with extrapulmonary cancer. Conclusion: In conclusion our results suggest that evaluation of tumor marker combinations may be useful in order to differentiate malignant pleural fluids.