This study examined the effects of ischemic preconditioning (IPC), allopurinol (Allo) or a combination of both on the extent of mitochondrial injury caused by hepatic ischemia/reperfusion (I/R). I/R increased the serum aminotransferase activity and the level of mitochondrial lipid peroxidation, whereas it decreased the mitochondrial glutathione level. Either IPC or Allo alone attenuated these changes with Alto + IPC having a synergistic effect. Allo increased the serum nitrite and nitrate level after brief ischemia. The significant peroxide production observed after 10 min of reperfusion after sustained ischemia was markedly attenuated by Allo + IPC. The mitochondria isolated after I/R were swollen, which was reduced by Allo + IPC. At the end of ischemia, the hepatic ATP level was lower and there was significant xanthine accumulation, which was attenuated by Allo + IPC. These results suggest that IPC and Allo act synergistically to protect cells against mitochondrial injury and preserve the hepatic energy metabolism during hepatic I/R. (c) 2006 Elsevier Inc. All rights reserved.