To examine whether antioxidant capacity is reduced in patients with schizophrenia, we determined plasma total antioxidant status (TAS) by quenching the absorbance of the radical cation formed by the reaction of 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) with a metmyoglobin and hydrogen peroxide. TAS serves as an index of net antioxidant activity derived from various antioxidants in plasma. Male schizophrenic patients were compared with age- and sex-matched healthy control subjects, using a within-subject, repeated measures, on-off-on haloperidol treatment design. Drug-free patients were free of all psychotropic medications for an average of 32 days. Plasma TAS was significantly lower in patients with schizophrenia than in normal controls. Plasma TAS in patients was significantly and inversely correlated with symptom severity during the drug-free condition. There were no significant differences between on and off haloperidol-treatment conditions. When patients returned to haloperidol treatment after relapse, the plasma TAS remained fairly constant and was not significantly different from the same individuals during haloperidol-stabilization or drug-free periods. These findings are indicative of an impaired antioxidant defense system, not attributable to neuroleptic treatment, and lend further support to the notion that oxidative stress may have a pathophysiological role in schizophrenia.