Vascular endothelial growth factor (VEGF) is known as a fundamental regulator of angiogenesis that accelerates cellular proliferation, vascular permeability, and endothelial cell migration and is an inhibitor of apoptosis. Extracellular matrix degradation by matrix metalloproteinase (MMP) is necessary for endothelial cell proliferation, migration, and metastasis. Accordingly, the objective of the present study was to determine the circulating levels of VEGF and MMP3 and their relation in patients with oral squamous cell carcinoma. Using an ELISA kit, the circulating levels of VEGF and MMP-3 in the sera of 45 patients with oral squamous cell carcinoma (OSCC) and 45 healthy controls were assessed. Mean VEGF levels in the sera of patients with OSCC (122.4 ± 36.1) were significantly higher than those in controls (65.3 ± 23.4); however, no relation was found between VEGF levels and clinicopathologic factors. The serum MMP-3 level in OSCC patients was significantly higher (9.45 ± 4.6 ng/ml, n=45) than that in healthy controls (5.9 ± 3.6 ng/ml, n=45). There was no correlation in serum MMP-3 concentration with clinicopathologic features such as tumor stage, tumor size, nodal status, and histological grade. A significant relationship was found between serum levels of VEGF and MMP3. This study concludes that VEGF and MMP3 may have a potential role in the pathogenesis of OSCC but cannot be used as a tool for monitoring tumor progression. Moreover, the role of VEGF in the regulation of angiogenesis is in part due to activation of MMP-3.