Vascular endothelial growth factor (VEGF), a potent inducer of angiogenesis and vascular permeability in diverse physiological and pathological conditions, may be involved in the pathophysiology of chronic subdural hematoma (CSDH). The present study investigated the source and mechanisms for the induction of VEGF in CSDH by measuring the concentration of VEGF in the hematoma of 102 patients (122 hematomas) using the enzyme-linked immunosorbent assay technique. The relationship between the VEGF concentration in hematoma and the intrahematoma membranous structure confirmed by preoperative T(2)(*)-weighted magnetic resonance image was examined in 46 of these patients. VEGF and hypoxia-inducible factor-1alpha (HIF-1alpha) expression was immunohistochemically studied and microvessel density (MVD) in the outer membrane was identified using anti-CD31 antibody in 30 patients. VEGF and HIF-1alpha were positive in the outer membranes of all 30 patients. VEGF expression was significantly correlated to HIF-1alpha expression (r(s) = 0.651, p = 0.0084) and VEGF concentration in the hematoma (r(s) = 0.654, p = 0.0013). VEGF concentration in layered hematomas, which have intrahematoma membranous structure, was significantly higher than in non-layered hematomas (p < 0.01). Although MVDs of the outer membranes were comparable to those described in tumors, there was no significant relationship with VEGF expression. The present study suggests that VEGF in CSDH, which may be induced in the neomembrane by HIF-1 release, may give rise to the excessive development of fragile microvessels and hyperpermeability, resulting in the enlargement of CSDH.