There is evidence of derangement of oxidant and antioxidant defense systems in depression. The present study examined the effects of fluoxetine and citalopram, standard selective serotonin re-uptake inhibitors, on lipid peroxidation, superoxide dismutase (SOD) activity and ascorbic acid concentrations. For this, a prospective open-labeled, randomized design was utilized. Patients with major depression (n = 62) were compared with age- and sex-matched healthy volunteers (n = 40). There was a significant increase in serum SOD, serum MDA and decrease in plasma ascorbic acid levels in patients of major depression as compared to control subjects. The trend reversed significantly after treatment with fluoxetine and citalopram. Results indicate a greater reduction in oxidative stress with citalopram than fluoxetine. The Hamilton Rating Scale for Depression (HRSD) score also improved with fluoxetine and citalopram treatment. These findings indicate that major depression is associated with increased levels of serum SOD, serum MDA and decreased levels of plasma ascorbic acid. Treatment with fluoxetine and citalopram reversed these biochemical parameters. This study can be used as a predictor of drug response by fluoxetine and citalopram in major depression.