This study was designed to determine the protective effect of melatonin treatment against oxidative damage in rat brain induced by hyperhomocysteinemia (Hhcy). Oral administration of methionine and its degradation product, homocysteine (hcy), causes mild to moderate Hhcy. The major end-point of oxidative damage measured in this report was lipid peroxidation (LPO). The levels of malondialdehyde (MDA) were assayed as index of lipid peroxidation. The increase in lipid peroxidation was inhibited by melatonin. Rats were divided into seven groups: one was used as control and each remaining group was supplemented with methionine dissolved and added to the drinking water daily for 4 weeks (0.5, 1, 1.5, 2, 3 g /kg BW). Additional groups of rats were given both melatonin (30 mg/kg BW) and methionine in drinking water daily. At the conclusion of the study, MDA levels were significantly increased in the brains of methionine-treated rats compared with control rats, whereas melatonin prevented the increases in MDA levels. Plasma hcy levels in animals treated with melatonin were significantly lower than those of controls. Melatonin lowered plasma hcy levels and could potentially be beneficial in prevention of neurodegeneration caused by mild hyperhomocysteinemia.