Pleural effusion (PE) representing extreme fluid detention in the pleural cavity, is a common medical issue that divided into "transudates" and "exudates". Recognizing the type of PEs is an essential intervention to prevent unnecessary and invasive diagnostic procedures that cause health care costs and complications. Increased vascular permeability is one of the main mechanisms in the production of PE which a multi-functional cytokine named vascular endothelial growth factor (VEGF) has a significant role in its pathogenesis. This study aimed to compare the pleural levels of VEGF in transudative and exudative PE besides the other pleural markers, trying to accurize the classification of pleural fluid.Materials and Methods: In the current cross-sectional study, ۸۰ patients with PE via the ability of tapping, were evaluated in a purposive manner in Ghaem Hospital, Mashhad, Iran, during ۲۰۱۳. The participants with coagulation disorder (international normalized ratio (INR) more than ۲ and platelets less than ۱۰۰,۰۰۰ per microliter), or patients with malignancy undergoing chemotherapy with anti-VEGF drugs were excluded. Before the thoracentesis, all cases signed informed consent. Then the patients were divided into ۴ groups as transudative (n=۱۵), parapneumonic (n=۱۵), tuberculosis (n=۲۵), and malignant PE (n=۲۵) based on the results of biochemical markers analysis of pleural fluid, pleural biopsy, medical history, and clinical signs. At last, the pleural VEGF level was measured by enzyme-linked immunosorbent assays (ELISA) after heparinizing, centrifuging, and freezing at -۲۰°C. This study was approved by the Mashhad University of Medical Science Ethics Committee. Data were analyzed using Chi-square, t-test, ANOVA, and Pearson tests in IBM SPSS v.۱۵ and significance was set at P=۰.۰۵.Findings: A mean age of ۵۵.۳۴ ± ۱۸.۵۳ years was assigned for ۸۰ eligible participants (including ۶۳.۷۵% male). Pleural VEGF levels were not correlated with age, gender, and positive cytology rate (P=۰.۴۰۲, P=۰.۱۰۹, and P=۰.۱۴۶, respectively). There were significant differences in pleural VEGF between transudative and exudative effusions (r=-۹۱۹۶.۷۸, P<۰.۰۰۱), and also between benign and malignant effusions (r=-۸۹۹۴.۶۱, P=۰.۰۱۴). Additionally, the pleural VEGF was significantly higher in malignant comparing tuberculosis effusions (P=۰.۰۰۵). In this study, VEGF higher than ۷۳۰۹ pg/dl had a ۶۴% sensitivity and ۸۲% specificity for the diagnosis of malignancy.Conclusion: This survey confirms that VEGF may be assumed as an important factor in the differential diagnosis of PEs, especially malignant effusion. Moreover, it can be used for discriminating different lymphocytic exudative PE. Nevertheless, this evidence should be further assessed in larger investigations to determine VEGF efficacy in the diagnosis of effusions