The mechanisms underlying alcoholic liver disease are not completely understood, but lipid accumulation seems to be central to the cause of this disease. The peroxisome proliferatoractivated receptor α (PPARα) plays an important role in the control of lipid homeostasis, metabolism of bioactive molecules, and modulation of inflammatory responses. To investigate the roles of PPARα in alcoholic liver injury, wild-type and PPARα-null mice were continuously fed a diet containing 4% ethanol, and liver injury was analyzed. PPARα-null mice fed ethanol exhibited marked hepatomegaly, hepatic inflammation, cell toxicity, fibrosis, apoptosis, and mitochondrial swelling. Some of these hepatic abnormalities were consistent with those of patients with alcoholic liver injury and were not found in wild-type mice. Next, the molecular mechanisms of ethanol-induced liver injury in PPARα-null mice were investigated, and changes related to ethanol and acetaldehyde metabolism, oxidative stress, inflammation, hepatocyte proliferation, fibrosis, and mitochondrial permeability transition activation occurred specifically in PPARα-null mice as compared with wild-type mice. In conclusion, these studies suggest a protective role for PPARα in alcoholic liver disease. Humans may be more susceptible to liver toxicity induced by ethanol as PPARα expression in human liver is considerably lower compared to that of rodents. (Hepatology 2004;40:972–980).