Diets supplemented with polyunsaturated fatty acids or triglycerides exacerbate alcohol-induced liver injury in rats, whereas, in baboons, polyenylphosphatidylcholine (PPC) protects against alcohol-induced fibrosis and cirrhosis. Because the aggravation in rats was attributed to enhanced lipid peroxidation, the present study was undertaken to assess parameters of oxidative stress in percutaneous liver biopsies of baboons fed alcohol, with or without PPC (2.8 g per 1000 calories). F2-isoprostanes and 4-hydroxynonenal, breakdown products of lipid peroxidation, were determined by gas chromatography/mass spectrometry, and alpha-tocopherol was measured by HPLC with electrochemical detection. Hepatic 4-hydroxynonenal was significantly increased in animals fed alcohol, but this was fully prevented by PPC. F2-isoprostanes were also significantly lower after PPC and ethanol than after ethanol alone, and the alcohol-induced glutathione decrease was attenuated. All of these parameters were normal in the animals withdrawn from alcohol, even with persistence of significant liver disease. Because peroxidation products are fibrogenic, their decrease could contribute to the antifibrogenic property of the phospholipids. In conclusion, PPC significantly attenuates ethanol-induced oxidative stress, which may explain, at least in part, its protective effect against alcoholic liver injury.