Cardioprotection by allopurinol during ischemia is thought to be due to inhibition of xanthine oxidase-derived reactive oxygen intermediates. Previous studies have reported that long pretreatment with allopurinol limits tissue necrosis during acute myocardial ischemia. This study investigated whether a prolonged pretreatment with allopurinol was necessary for cardioprotection. Tissue necrosis was measured in a closed chest canine model of permanent coronary occlusion when the drug was administered post coronary occlusion. In 20 dogs the coronary artery was occluded by an embolus injected into the left coronary artery. Three groups were studied: untreated controls (saline given intravenously post occlusion); allopurinol 1 min post occlusion (25 mg/kg given intravenously, 1 min post occlusion); and allopurinol 30 mins post occlusion (25 mg/kg given intravenously 30 mins post occlusion). Dogs in both drug treatment groups also received allopurinol (25 mg/kg intravenously) every 8 h post coronary occlusion. After 24 h of permanent coronary occlusion tissue necrosis was evaluated using triphenyl tetrazolium chloride staining and was related to major baseline predictors of infarct size, including anatomic risk zone and coronary collateral flow. In control dogs, infarct to risk zone ratio was inversely related to subepicardial collateral flow; analysis of covariance indicated that allopurinol administered post coronary occlusion did not shift this relationship. Treatment with allopurinol within the first minutes after coronary occlusion was ineffective in limiting tissue necrosis in this model of permanent coronary occlusion, therefore, long pretreatment with allopurinol is necessary for cardioprotection.