Some reports have shown that schizophrenia is accompanied by the abnormal metabolism of free radicals. The purpose of this study was to investigate the effect of the atypical antipsychotic drug risperidone on blood superoxide dismutase (SOD), a critical enzyme in the detoxification of superoxide radicals, and to explore the relationship between changes in SOD and the therapeutic outcome. Forty-one inpatients with diagnosed schizophrenia (DSM-III-R) were assigned to 12 weeks of treatment with risperidone at a fixed dosage of 6 mg/d after a 2-week washout period. Clinical efficacy was determined with the Positive and Negative Syndrome Scale (PANSS). Blood SOD was assayed by radioimmunoassay (RIA) in schizophrenic patients before and after the 12-week treatment, and the values were compared with those of 50 age-, sex-, and smoking-matched subjects without schizophrenia. Risperidone treatment significantly decreased the initially high blood SOD levels in schizophrenia. There was a significantly positive relationship between the change in SOD at pretreatment and posttreatment and the reduction in the PANSS negative subscore. These findings suggest that risperidone treatment significantly decreased the blood SOD levels of schizophrenic patients, a change which may be associated with the diminishment of symptoms. The limitations of this study are the measurement of SOD levels by RIA rather than biochemical assay; the 2-week washout, which may not be adequate; and the measurement of only SOD enzyme and not the other antioxidant enzymes.