In order to study the tolerance of the blood-brain barrier to microwave irradiation at 2450 MHz, and to determine the upper limits of time and temperature for application of microwaves without excessive disruption of the barrier, an experimental model was developed. The rat's head was heated selectively in the near field by shielding the remainder of the body. Brain and body-core temperatures were monitored via thermocouples. An enzymatic tracer protein, horseradish peroxidase, was administered intravenously (0.18 g kg−1) 30 minutes before an animal was euthanized. Biochemical quantitation of extravasated peroxidase in homogenized brains of animals, which had been perfused through the aorta with 5% PVP in saline at 4°C to purge intravascualr blood and tracer, was the index of barrier permeation. In initially normothermic (37°C) animals, barrier integrity was diminished after heating of brains for 10 minutes at 45°C, after 15 minutes at 42°C, and after 60 minutes at 40°C. In precooled (30°C) rats, mortality and barrier integrity were diminished after heating brains for 15 minutes at 45°C, after 30 minutes at 42°C, and after 180 minutes at 40°C. Microwave-induced hyperthermia apparently increased the permeability of the blood-brain barrier to protein, but less so when the lower body was cooled. The tolerance of the barrier to microwave irradiation is dose-related and is dependent on the temperature to which the brain is heated and on the length of time during which that temperature is maintained. The barrier received significant protection from body-core hypothermia, probably through cooling of endothelial cells by circulating blood.