We studied the possible role of prior ischemic stress as a protective mechanism against cerebral infarction in rats. Two brief periods of global cerebral ischemia, separated by 24 h, did not cause cell death in brain, but did produce neuronal stress, as demonstrated by induction of the nonconstitutive 72 kDa heat shock protein (HSP72). Forty-eight hours later, animals subjected to prior ischemia had smaller infarct from permanent middle cerebral artery occlusion than did sham-operated controls. These findings support an association between ischemia-induced stress, HSP72 induction, and attenuation of injury from subsequent focal cerebral ischemia.