Nonsteroid anti inflammatory drugs (NSAID) are commonly used in the world. These drugs sometimes may be used in high or toxic doses by mistake. This experimental study was performed to investigate the effect of high dose diclofenac sodium, a NSIAD, on erythrocyte lipid peroxidation and antioxidant enzymes. Fourteen male rats were divided in two groups. Single dose of 125 mg/kg diclofenac sodium was given intramuscularly to the study group and physiologic saline was applied to the control group in the same volume. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GR), catalase (CAT) and glucose-6-phosphate dehydrogenase (G6PD) and the level of malondialdehyde (MDA) were measured after 24 hours of administration. The activities of SOD and G6PD and the level of MDA were found to be significantly higher in study group than control group (p<0.001, p<0.05, p<0.01, respectively). These results suggest that high dose of diclofenac sodium causes a meaningful induction on erythrocytes antioxidant defense system. But, this induction is not enough to scavenge free radicals, thus it seems not to protect the cells from the lipid peroxidation.