P>Three days of fasting protects mice against lethal renal ischemia-reperfusion (I/R) injury. We hypothesize that the protection imposed by fasting is mediated by increased levels of corticosterone, induced by the stress of food deprivation. C57Bl/6 mice were fasted for 3 days after which serum corticosterone levels were determined. Mice underwent a bilateral adrenalectomy (ADX). Ten days later, they were either fasted or given a corticosterone receptor antagonist while fasting. Bilateral renal I/R injury was induced by clamping the artery and vein of the left and right kidney simultaneously for 37 min. Survival and kidney function were determined. Fasting significantly increased corticosterone levels. Only 8% of the ADX mice which were fasted prior to I/R injury survived, whereas all sham-ADX operated mice survived I/R injury after fasting. After ADX and fasting, 70% of the mice subjected to sham I/R succumbed to the surgical procedure. After fasting with concomitant blockade of the glucocorticoid receptor all animals survived renal I/R. Three days of fasting protects against I/R injury and increases serum corticosterone levels. ADX renders mice incapable of withstanding subsequent abdominal surgery. Glucocorticoid receptor blockade does not interfere with the protective effects of fasting. Thus, the protection against renal I/R injury induced by preoperative fasting is mediated by corticosterone-independent mechanisms.