BACKGROUND Tardive dyskinesia (TD) is a therapy-resistant adverse effect of neuroleptics. Although the exact pathophysiology of TD is unknown, oxygen radicals have been speculated to play a role in TD based on several lines of evidence. Superoxide dismutase (SOD) is a key enzyme which scavenges oxygen radicals. The authors investigated the association between erythrocyte SOD activity and TD. METHODS Erythrocyte SOD activities were measured, blinded as to the presence or absence of TD. In 30 patients with schizophrenia who had been on typical neuroleptics for more than 10 years. TD severity was independently assessed, using the abnormal involuntary movement scale (AIMS), by two raters. RESULTS There was a significant decrease in erythrocyte SOD activity in the definite TD group (N = 10) as compared with the no TD (N = 8) and questionable TD (N = 12) groups. Erythrocyte Cu,Zn-SOD activities correlated with AIMS scores. CONCLUSIONS Patients with TD had low SOD activities as compared to those without TD. As a causal link between SOD activity and TD was not established in this study, larger prospective studies are warranted to determine whether patients with low SOD activity are susceptible to neuroleptic-induced TD.