Alcohol is associated with accidental deaths and suicides leading to organ donation, and hepatic steatosis is an important risk factor for initial poor function and failure of human liver grafts. Mechanisms of fatty graft failure are not fully understood, but increased oxidative stress may be a major factor. To characterize the role of free radical stress and the efficacy of antioxidant treatments in fatty liver graft injury, donors for orthotopic rat liver transplantation were treated chronically (3 or more weeks) and acutely (single dose) with ethanol. After transplantation, necrosis and alanine aminotransferase release were threefold to fourfold higher in recipients of fatty grafts from donors treated with ethanol either acutely or chronically compared with findings for recipients of grafts from untreated donors. Moreover, graft survival decreased from nearly 100% to less than 20%. Free radical adducts, as measured by electron spin resonance spectroscopy, were detected in the blood and bile of rats receiving fatty grafts caused by ethanol. Markers of lipid peroxidation also increased after transplantation. Destruction of Kupffer cells with gadolinium chloride decreased free radical production and improved graft survival. Leukocyte adhesion increased beginning early after implantation, and adherent white blood cells obtained from transplanted fatty livers produced the same free radical species as were detected in blood. Therefore, Kupffer cells and adherent white blood cells are important sources of free radicals. Free radicals not only damage fatty grafts directly but also lead to enhanced inflammation and disturbed microcirculation. Delivery of superoxide dismutase-1 and superoxide dismutase-2 genes, free radical-scavenging polyphenols, and antioxidant-containing Carolina Rinse solution reduced injury and improved survival of fatty grafts caused by ethanol. Taken together, these findings indicate that free radicals increase in fatty grafts after transplantation and play an important role in injury of fatty grafts obtained from ethanol-exposed donors. Treatment of fatty donor livers with antioxidants and free radical scavengers may thus be an effective clinical therapy to prevent failure of fatty grafts.