Background: Cancer Antigen-125 (CA-125) was first identified as an ovary-specific tumor indicator but subsequently shown that inflammation exists even in the absence of polymorphism leads to this marker to rise. Multiple locations of tuberculosis (TB) produce an increase in serum antigen levels. This research objects to estimate the diagnostic value of CA-125 and to establish the cut-off value, distinguishing tuberculous from malignant pleural effusion. Methods: This prospective analytic case control study involved 90 subjects above 18 years old and with a confirmed diagnosis of tuberculous pleural effusion (TPE), malignant pleural effusion (MPE) and parapneumonic effusion (PPE). Subjects were equally allocated into 3 groups: group I "Tuberculous": subjects with a confirmed diagnosis of TPE, group II "Malignant": subjects with a confirmed diagnosis of MPE and group III "Control": subjects with a confirmed diagnosis of PPE. Results: There was positive significant correlation among CA-125 in serum and pleural fluid in tuberculous effusion group (group I) and in malignant effusion group (group II). Conclusions: For reliable detection of pleural effusion cause, serum and pleural fluid CA-125 might be included to the pleural fluid diagnostic workup.