Background Pleural effusion can arise as a result of more than 50 recognized causes and the differentiation between benign and malignant origin of the fluid is still a diagnostic challenge. The ability of tumor markers and other biological markers to make better diagnosis of malignant pleural effusion (MPE) remains questionable. Out of these, the calcium-related proteins S100-A8 and S100-A9 (the noncovalent heterodimer calprotectin) were demonstrated in a small amount in malignant not in benign pleural effusion. Objectives This research aimed to assess the diagnostic value of calprotectin in the differentiation between infectious or benign and MPE. Patients and methods Sixty patients were divided into group I: malignant and group II: infectious pleural effusions (which were further divided into group IIA: parapneumonic effusion and group IIB: tuberculous effusion) Quantitative measurement of calprotectin was done using the enzyme-linked immunosorbent assay technique in pleural effusion. Results Pleural calprotectin level in MPEs (229.2±168.6 ng/ml) was significantly lower than its level of infectious pleural effusions (3202.2±1304.8 ng/ml; P