One of the major problems associated with long-term neuroleptic treatment is persistent tardive dyskinesia (TD), for which there is no satisfactory treatment. We have recently proposed that some cases of TD are associated with neuronal dysfunction resulting from excess free radical production occurring during catecholamine metabolism. We therefore decided to assess the efficacy of a powerful free radical scavenging agent, α-tocopherol (vitamin E), on the clinical signs of TD. We treated 15 patients with persistent TD with α-tocopherol and matched placebo in a randomized crossover design. Patients demonstrated a significant overall reduction in scores on the Abnormal Involuntary Movements Scale (AIMS) after treatment with α-tocopherol, but not after placebo. The mean reduction in the AIMS score with α-tocopherol was 43 percent, with seven patients showing a greater than 50 percent reduction in their dyskinesia. There was also a trend for a decrease in scores on the Brief Psychiatric Rating Scale, but no change was observed in scores on the Simpson-Angus Scale for Extrapyramidal Side Effects. Our findings are consistent with the possibility that α-tocopherol is beneficial in the treatment of some patients with TD, but further research is necessary to establish the efficacy of this agent.