Atherosclerosis may cause severe stenosis of the arteries supplying the brain, which induces chronic cerebral hypoperfusion. Although an infarction often occurs in the chronically hypoperfused brain area, it has been uncertain whether the stroke severity is attenuated or increased when further decrease of blood flow occurs. To test the hypothesis that chronic cerebral hypoperfusion is protective against the subsequent severe ischemia, we examined the effect of chronic cerebral hypoperfusion on brains subjected to acute focal ischemia. Spontaneous hypertensive rats were subjected to middle cerebral artery occlusion/reperfusion four weeks after bilateral common carotid artery ligation (BCAL) or sham operation. The rats with BCAL had smaller infarctions, determined by 2,3,5- triphenyltetrazolium hydrochloride staining, and less severe neurologic deficits than those with sham operation. The number of DNAdamaged cells, examined by the in situ nick translation study, was significantly reduced in animals with BCAL. Immunoreactivity for apurinic/apyrimidinic endonuclease/redox factor-1, which plays a role in cellular defense mechanism, was markedly increased in those with BCAL. Indirect evidence of extracellular matrix remodeling, which might be associated with adaptive arteriogenesis or angiogenesis, was obtained in the form of increased matrix metalloproteinase-2 activity in them. These findings provide experimental evidence that chronic cerebral hypoperfusion would be protective against subsequent severe ischemic insults.