A rabbit model of focal temporary ischemia was used to test the protection provided by mild hypothermia, hypertension, mannitol and the combination of the three methods. Twenty-four New Zealand White rabbits were divided into five groups as follows: a control group, a hypertension group (mean arterial blood pressure increased by 42 mm Hg), a hypothermic group (rectal temperature decreased by 6 degrees C), a mannitol group (1 g/kg of body weight, administered intravenously), and the triple-therapy group. The intracranial internal carotid artery, the middle cerebral artery, and the anterior cerebral artery were clipped for 2 hours and then underwent 4 hours of reperfusion. Blood pressure, rectal and brain temperature, blood glucose level, hematocrit, and arterial blood gases were monitored during the experiment. For measuring the infarction size, the brain was divided into 4-mm slices and stained with 2,3,5-triphenyltetrazolium chloride. The severity of the neuronal damage was also evaluated by conventional histological examination with hematoxylin and eosin staining. The infarct volume was 193.2 +/- 34.8 (standard error of the mean) mm3 for the control group, 32.3 +/- 22.6 mm3 for the hypertension group (P < 0.0005 versus control), 40.9 +/- 17.6 mm3 for the hypothermia group (P < 0.0005), 58.0 +/- 41.0 mm3 for the mannitol group (P < 0.005), and 0.9 +/- 0.9 mm3 for the triple-therapy group (P < 0.0001). The infarct volume of the triple-therapy group was smaller than that of the hypertension, hypothermia, and mannitol groups but the difference was not statistically significant. The combination of hypertension, mild hypothermia, and mannitol to protect against temporary focal ischemia provides a set of manipulations that is readily available for neurovascular procedures.