The purpose of this study was to document the early cerebrovascular consequences of excessive N-methyl-D-aspartate (NMDA) receptor activation. Five microliters of NMDA (100 nmol/microliters) or vehicle was infused over a 15-min period into the lateral ventricle of adult rats. The protein tracer horseradish peroxidase (HRP) was injected intravenously for blood-brain barrier (BBB) studies. The intraventricular infusion of vehicle (n = 5) caused no alterations in arterial blood pressure or microvascular damage away from the intraventricular probe tract. In contrast, NMDA infusion (n = 8) led to a gradual increase in arterial blood pressure (mean 36 mm Hg). Multifocal regions of HRP extravasation were observed bilaterally throughout the neuraxis following NMDA infusion. Sites of BBB disruption and hemorrhage included brain regions bordering ventricular spaces. In addition, isolated foci of protein extravasation were commonly detected in the cerebral cortex, thalamus, basal forebrain, septum and cerebellum. Pretreatment with the noncompetitive NMDA antagonist MK-801 (2 mg/kg) substantially reduced the BBB responses to NMDA. However, microvascular abnormalities were seen in NMDA-infused rats where blood pressure elevations were inhibited by blood removal. In addition to neurons, cerebral blood vessels are also acutely affected by NMDA receptor activation. Blockage of NMDA receptor channels following brain injury may potentially provide protection by attenuating BBB breakdown and subsequent brain edema.