The cell type and localization of vascular endothelial growth factor (VEGF)-producing cells in human radiation necrosis (RN) are investigated from a histopathological and immunohistochemical standpoint using clinical specimens. Eighteen surgical specimens of symptomatic RN in the brain were retrospectively reviewed. These cases included different original histological tumor types and were treated with different radiation modalities. Histological analyses were performed using hematoxylin and eosin (H&E) staining, and anti-VEGF and anti-hypoxia-inducible factor (HIF)-1α immunohistochemistry. H&E staining showed marked angiogenesis and reactive astrocytosis at the perinecrotic area. The most prominent vasculature in this area was identified as telangiectasis. Immunohistochemistry indicated that HIF-1α was expressed predominantly in the perinecrotic area and that a large majority of VEGF-expressing cells were reactive astrocytes intensively distributed in this area. VEGF produced by the reactive astrocytes localized mainly in the perinecrotic area might be a major cause of both angiogenesis and the subsequent perilesional edema typically found in RN of the brain. The benefits of anti-VEGF antibody (bevacizumab) treatment in RN may be that VEGF secretion from the perinecrotic tissue is inhibited and that surgery would remove this tissue; both of these benefits result in effective reduction of edema associated with RN.