The effect of melatonin administration on the oxidative stress induced by a high dose of Adriamycin (AD, doxorubicin hydrochloride) in plasma, hypothalamus and brain cortex of rats, as well as lipoperoxide changes, and catalase activity (CAT) levels have been studied. After administration of a single high AD dosis (25 mg/kg, i.p.), melatonin was injected daily three days before and after oxidative stress induction. The AD injection produced a significant lipoperoxide increase in plasma, hypothalamus and brain cortex, which was prevented by melatonin. CAT activity mean values decreased in hypothalamus by AD, effect which was reverted and increased by simultaneous melatonin administration. CAT activity was not changed after AD, melatonin or AD + melatonin administration in plasma and brain cortex. These results, especially those concerning lipoperoxide content changes, showed a powerful antioxidative effect of melatonin at both neural and extraneural levels in rats. CAT changes in the presence of melatonin suggest that there is a relationship between a scavenger role of the pineal hormone and a high oxidative activity in the brain hypothalamy area. When these results are taken together, they also show that melatonin, besides, producing the extraneural effect, can act as a powerful antioxidative agent in organs such as the brain, very rich in lipid susceptible to oxidation in the neuronal as well as the extraneuronal tissues.