The diagnostic value of the novel tumor marker CYFRA 21-1 in malignant pleural fluid was assessed in comparison to carcinoembryonic antigen (CEA). CYFRA 21-1 and CEA were measured in pleural fluid obtained from patients with 108 malignant and benign diseases. The levels of pleural fluid CYFRA 21-1 in malignant diseases (median: 84.5 ng/ml) were statistically higher than those in benign diseases (median: 13.9 ng/ml; p < 0.01). The CYFRA 21-1 test was able to discriminate significantly between squamous cell lung cancer and pneumonia (p < 0.01), while pleural fluid CEA levels could not. Receiver operating characteristic (ROC) curve analysis showed that the CYFRA 21-1 test has an advantage over CEA because of its higher specificity. These results indicate that measurement of CYFRA 21-1 in pleural fluid is a new tool, in addition to cytologic examination, to discriminate between malignant and benign diseases.