Objective To explore the clinical significance of combined detection of CEA, CYFRA21-1, CA19-9 and Fer in the differential diagnosis of benign pleural effusion and malignant ones. Methods The serum levels of CEA, CYFRA21-1, CA19-9 and Fer in 53 patients with malignant pleural effusion and 41 patients with benign pleural effusion were detected by chemiluminescence detection technology. Results The serum levels of four items in malignant pleural effusion group were significantly higher than those of the benign group (P < 0. 01). The positive rates of CEA, CYFRA21-1, CA19-9 and Fer in the diagnosis of malignant pleural effusion were 75. 47% , 77.35% , 66. 03% and 52. 8% respectively. The positive rate of combined detection of four items was 90. 1% . Conclusion The combined detection of CEA, CYFRA21-1 , CA19-9 and Fer present higher contents in malignant pleural fluid which play a role in differential diagnosis between malignant and benign pleural effusion.