To test whether the ischemic acute renal failure (IARF) kidney has increased susceptibility to additional ischemic events, IARF was induced in female Sprague-Dawley rats [40 min of bilateral renal artery occlusion (RAO)] and either 18 or 48 hr later, at the height of morphologic injury, they were rechallenged with either 25 or 40 min of RAO. Changes in renal function (GFR, blood flow), morphology, and adenine nucleotide (AN) concentrations in response to these second ischemic challenges were compared to those of normal kidneys subjected to a single ischemic event. In additional experiments, rates of recovery from IARF were compared between rats subjected to one or two bouts of RAO (40 min, 24 hr apart). IARF kidneys retained a significantly greater percent of their baseline GFR and had comparable or higher absolute GFRs after 25 or 40 min of RAO than control rats. IARF rats showed no significant exacerbation of their underlying morphologic injury by superimposing a second ischemic event. IARF kidneys (24 hr post RAO) had normal AN concentrations, and by 30 min of reflow from a second 40 min of RAO, they re-established their AN energy charge and retained AN pools as well as control kidneys. A second 40-min bout of RAO did not significantly prolong recovery rates from the first 40-min ischemic event. In additional experiments, intraperitoneal injection of normal urine or solute matched artificial urine (urea, creatinine, NaCl) into normal rats to mimic the degree of azotemia seen in the IARF rats induced significant and comparable protection against 40 min of RAO. We conclude that the IARF kidney, at or near the height of its functional and morphologic injury, does not have increased susceptibility to additional ischemic insults. Rather a modicum of protection appears to exist, possibly due to renal-failure-induced increments in solute loads per nephron.