Background/Aim: Approximately 20% of pleural effusions are associated with cancer; about 50% require invasive procedures to perform diagnosis. Determination of the concentration of soluble cytokeratin 19-fragments (CYFRA21-1) may help identify patients with malignant effusions. However, pathologies other than cancer can increase its concentration. The identification of these possible false positives with routine tests CRP, ADA, % polymorphonuclear cells (PN) may improve diagnostic accuracy. This study aimed to determine the diagnostic accuracy of CYFRA21-1 in the detection of malignant pleural effusions and the possible false positives. Materials and Methods: Analysis of CYFRA21-1, adenosine deaminase (ADA), C-reactive protein (CRP), and the percentage of polymorphonuclear leukocytes (PN%) in the fluid from 643 consecutive undiagnosed pleural effusions was performed. Results: CYFRA21-1 showed 38.7% sensitivity and 97.3% specificity at 175 ng/ml cut-off. Effusions not suspicious of a false-positive showed 39.0% sensitivity and 98.2% specificity, while effusions suspicious of false positive showed lower sensitivity (36.4%) and specificity (95.0%). Conclusion: The diagnostic accuracy of CYFRA21-1 in pleural effusions can be improved by classification according to the possibility of false positives.Pleural effusions can be caused by a wide variety of diseases. Among them, cancer is one of the most frequent; with rates between 15% and 27% (1, 2). Differential diagnosis of pleural effusions is not easy. Cytology is the gold standard test for ruling out cancer, but its sensitivity is only moderate (between 45% and 70%) (2, 3). This means that more invasive tests are sometimes necessary, increasing morbidity and raising the economic cost. Soluble cytokeratin 19-fragments (CYFRA21-1) have been evaluated in the differential diagnosis of cancer in pleural effusions. The results vary widely from study to study; the specificity ranges between 7% and 100% and the sensitivity between 25% and 90%, using discriminant values between 3.3 ng/ml and 175 ng/ml (4-10). Most studies applying highly discriminant values (55-175 ng/ml) obtained sensitivities between 24% and 70% and specificities above 95% (6, 10-13). However, in diseases such as tuberculosis, empyema and parapneumonic effusions, as well as in inflammatory processes of the surrounding tissues, high concentrations of this tumor marker can be found in the pleural fluid (11,14,15). Some biomarkers suggest a benign diagnosis: examples are adenosine deaminase (ADA) in tuberculosis and empyema, white blood cell count and the percentage of polymorphonuclear leukocytes (PN%) in empyema and complicated parapneumonic effusions, and C-reactive protein (CRP) in all three of the above conditions, and in the process of necrosis or inflammation of the surrounding tissues.