Recent findings suggest that free radical-mediated pathological processes may underlie membrane deficits that have been observed in schizophrenia. We have previously demonstrated that both total antioxidant status (TAS) and individual antioxidants were significantly reduced in plasma of chronic schizophrenic patients, on and off haloperidol. To test whether reductions in plasma antioxidants are independent of treatment or illness progression, levels of plasma antioxidants were evaluated in 43 patients at first-episode of psychosis, 31 patients meeting DSM-IV criteria for schizophrenia or schizoaffective disorder (reconfirmed after 6 months) and 12 patients with primary mood (bipolar or depressive (BP/D)) disorder, at neuroleptic-naive baseline as well as 40 age- and sex-matched normal controls (NC). The major plasma antioxidants albumin, uric acid and bilirubin were all significantly lower in the first-episode schizophrenic, but not in the BP/D patients, than in normal controls. Factors that can affect these antioxidants-age, gender, diet and smoking-were examined. Body mass index (BMI) was significantly lower in patients, but was not correlated with plasma albumin and bilirubin; there was a trend for a correlation with uric acid in schizophrenic patients. Lower antioxidant levels were independent of smoking status of patients. The present data suggest that a defect in the antioxidant defense system (AODS), which may lead to oxidative damage, occurs early in the course of illness and is independent of treatment effects.