Objective: The diagnostic utility of the tumour marker CYFRA 21-1 in malignant pleural effusion is not yet clear. This study was designed to evaluate the diagnostic utility of serum and pleural fluid CYFRA 21-1 in malignant pleural effusion. Methodology: The validity of serum and pleural fluid CYFRA 21-1 was determined in 62 patients with exudative pleural effusion (27 malignant and 35 benign). The diagnosis of malignant pleural effusion was defined by cytological or histological results. Results: A statistically significant difference between the geometric means of CYFRA 21–1 levels in pleural fluid of benign and malignant aetiologies was observed (11.2 vs 63.3 ng/mL, P < 0.0001). In addition, there was a significant difference in the serum levels (0.95 vs 5.55 ng/mL, P < 0.0001). The sensitivity and specificity of pleural fluid CYFRA 21-1 in malignant pleural effusion, at the cut-off value of 55 ng/mL, was 74.1% and 97.1%, respectively. The sensitivity and specificity of serum CYFRA 21-1, at the cut-off value of 2.5 ng/mL, was 81.5% and 97.1%, respectively. Using a combination of serum and pleural fluid CYFRA 21-1 level, the sensitivity increased to 88.9%. Conclusion: Serum and pleural fluid CYFRA 21-1 are useful as measures in differentiating malignant from benign pleural effusion