Allopurinol (ALL) improves energy metabolism in organs subjected to ischemia-reperfusion injury. The importance of different administration schedules of ALL has been studied in a rat liver model exposed to 60 min of normothermic ischemia followed by reperfusion. ALL (100 mg/kg) that administered in two doses, one prior to ischemia and one prior to reperfusion, improved production of adenosine triphosphate in the liver as well as bile flow during reperfusion. ALL administered in a single dose, either prior to ischemia or prior to reperfusion, was less effective. The concentration of hypoxanthine during ischemia increased in the groups given ALL prior to induction of ischemia. Based on the present findings, we argue that the beneficial effect of ALL administration can be potentiated by different drug-administration schedules. Our data also suggest that the prime mechanism of action for ALL is not only related to inhibition of free-oxygen-radicals production but that preservation of hypoxanthine, which can be used for ATP resynthesis and the scavenging properties of ALL itself, may be equally important.