The detection of circulating nucleic acids has long been explored for the diagnosis of a variety of clinical conditions. The aim of this study was to detect the cell-free mRNA expression of BIRC5 in patients with effusions and assess its potential diagnostic value. Pleural fluids and ascites samples were collected prospectively from 112 patients. The cell-free RNA was extracted from effusions and the mRNA expression of BIRC5 was detected using real-time RT-PCR. The expression of carcinoembryonic antigen (CEA) and biochemical markers in effusions was also assayed. Effusions were classified as benign or malignant on the basis of their definitive pathologic or cytologic diagnoses. The expression of cell-free BIRC5 mRNA was statistically significantly higher in the malignant group than in the benign group. BIRC5 mRNA was also significantly different between patients with Stage III and Stage IV non-small cell lung cancers. The sensitivity and diagnostic accuracy of BIRC5 were 79.0 and 81.3%, whereas a combination of CEA and BIRC5 reached 86.4% sensitivity and 88.4% accuracy. These results indicate that effusions with higher levels of cell-free BIRC5 mRNA are more likely to be malignant. Determination of BIRC5 and CEA in effusions could enhance diagnostic value in the diagnosis of malignant effusions.