Liver ischemia reperfusion (I/R) injury is associated with profound arginine depletion due to arginase release from injured hepatocytes. The purpose of this study was to determine if arginase inhibition with N-Hydroxy-nor-L-arginine (nor-NOHA) would increase circulating arginine levels and decrease hepatic damage during liver I/R injury. The effects of nor-NOHA were initially tested in normal animals to determine in-vivo toxicity. In the second series of experiments, orthotopic syngeneic liver transplantation (OLT) was performed after 18 hour cold ischemia time (CIT) in Lewis rats. Animals were given nor-NOHA (100 mg/kg) or saline prior to and after graft reperfusion. In normal animals treated with nor-NOHA, there were no histopathologic changes to organs, liver enzymes, serum creatinine, or body weight. In the OLT model, animals treated with saline exhibited markedly elevated serum transaminases and circulating arginase protein levels. Nor-NOHA administration blunted the increase in serum arginase activity by 80%, and preserved serum arginine levels at 3 hours after OLT. Nor-NOHA treatment reduced post-OLT serum liver enzyme release by 50%. Liver histology (degree of necrosis) in nor-NOHA treated animals was markedly improved compared to the saline-treated group. Furthermore, use of the arginase inhibitor nor-NOHA did not influence polyamine synthesis due to the decrease in ornithine levels. Arginase blockade represents a potentially novel strategy to combat hepatic I/R injury associated with liver transplantation.