OBJECTIVE: Evidence suggests that the neuropathology of Huntington's disease, a neuropsychiatric disorder due to a mutation on chromosome 4, results from excessive activation of glutamate-gated ion channels, which kills neurons by oxidative stress. Therefore, the authors hypothesized that alpha-tocopherol, which reduces oxyradical damage to cell membranes, might slow the course of Huntington's disease. METHOD: A prospective, double-blind; placebo-controlled study of high-dose d- alpha-tocopherol treatment was carried out with a cohort of 73 patients with Huntington's disease who were randomly assigned to either d-alpha- tocopherol or placebo. Patients were monitored for changes in neurologic and neuropsychologic symptoms. RESULTS: Treatment with d- alpha-tocopherol had no effect on neurologic and neuropsychiatric symptoms in the treatment group overall. However, post hoc analysis revealed a significant selective therapeutic effect on neurologic symptoms for patients early in the course of the disorder. CONCLUSIONS: Antioxidant therapy may slow the rate of motor decline early in the course of Huntington's disease.