Brain edema is a potentially fatal pathological state after brain insults such as ischemia and trauma. However, the therapeutic strategy to prevent brain edema has not been established. Following brain insults, endothelins (ETs) are increased and promote several pathophysiological responses. The increases in brain ETs cause productions of vascular permeability factors, such as matrixmetalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) through ETB receptors. In this study, we examined the effects of ETB receptor antagonists on vasogenic brain edema. Vasogenic edema was induced in mice (5 to 6 week-old male ddY mice) by cold injury: a copper rod cooled by dry ice was attached to left cortical brain for 1 min. Brain edema was determined by water contents in the cerebrum. Permeability of brain microvessels was evaluated by extravasation of intravenous administrated Evans blue. The increases of water content and extravasation of Evans blue were observed in the injured cerebrum at 6 to 72 h after cold injury. Intracerebroventricular (ICV) administrations of ETB antagonists (BQ788 and IRL-2500) at 30 min prior to cold injury significantly attenuated the increase of water content and extravasation of Evans blue in 12 h after cold injury. Repeated administration of BQ788 and IRL-2500 started from 24 h after cold injury also attenuated the increase of water content and extravasation of Evans blue in 72 h after cold injury. ICV administrations of BQ788 and IRL-2500 also attenuated cold injury-induced increase of glial fibrillary acidic protein (GFAP)-positive reactive astrocytes in the injured cerebrum. Cold-injury increased productions of MMP9 and VEGF-A in the cerebrum. The immunohistochemical observations indicated that the expressions of MMP9 and VEGF-A were observed in reactive astrocytes in 12 h and 72 h after cold injury. ICV administration of BQ788 and IRL-2500 reversed the cold injury-induced increase of MMP9 and VEGF-A. These results suggest that ETB antagonists ameliorate the formation and maintenance of vasogenic brain edema through attenuation of astrocytic MMP9 and VEGF-A expressions.