Our goal was to determine the role of vascular endothelial growth factor (VEGF) in diagnosing of pleural effusion (PE) in order to select patients deserving of more aggressive procedures. Seventy-nine consecutive patients with undiagnosed unilateral PE were enrolled. Pleural VEGF levels, measured using enzyme-linked immunosorbent assay (ELISA), were correlated to etiology of PEs and other markers (protein, lactic dehydrogenase, amylase, glucose). The median level of VEGF in exudates (n=65) was significantly higher than that in transudates (P=0.0001) and among exudates, it was significantly higher in malignant (n=49) than that in benign exudates (P=0.005). No significant differences were observed between malignant effusions due to lung cancer (n=11) and other malignant effusions [mesothelioma (n=13) and/or extra-thoracic cancer]. Among all variables evaluated, logistic regression found that only VEGF was significantly correlated with the presence of malignant disease (P=0.002). Analysis of the receiver operating characterists (ROC) curves showed that the areas under the curve of VEGF were significantly larger than that of amylase (P=0.02), glucose (P=0.01), lactic dehydrogenase (P=0.001) and protein (P=0.01). VEGF increased the diagnostic rate of cytological examination by 24%. VEGF may represent a helpful adjunct to conventional diagnostic tools in ruling out malignancy as a probable diagnosis, thus guiding the selection of patients who might benefit from further invasive procedures.