α-Tocopherol transfer protein (α-TTP) maintains the concentration of serum α-tocopherol (vitamin E), one of the most potent fat-soluble antioxidants, by facilitating α-tocopherol export from the liver. Mutations of the α-TTP gene are linked to ataxia with isolated vitamin E deficiency (AVED). We produced a model mouse of AVED by deleting the α-TTP gene, which showed ataxia and retinal degeneration after 1 year of age. Because the brain α-TTP functions in maintaining α-tocopherol levels in the brain, α-tocopherol was completely depleted in the α-TTP^−/− mouse brain, and the neurological phenotype of α-TTP^−/− mice is much more severe than that of wild-type mice when maintained on an α-tocopherol-deficient diet. Lipid peroxidation in α-TTP^−/− mice brains showed a significant increase, especially in degenerating neurons. α-Tocopherol supplementation suppressed lipid peroxidation and almost completely prevented the development of neurological symptoms. This therapy almost completely corrects the abnormalities in a mouse model of human neurodegenerative disease. Moreover, α-TTP^−/− mice may prove to be excellent animal models of delayed onset, slowly progressive neuronal degeneration caused by chronic oxidative stress.