To investigate the role of melatonin in D-galactose-induced amnesic mice, the avoidance/escape and water maze tests were performed to evaluate their learning and memory function. Spectrophotometry was employed to determine the content of thiobarbituric acid-reactive substances (TBARS) and the activities of antioxidative enzymes in the brain. The present results demonstrate that D-galactose-induced amnesic mice had significantly decreased learning and memory function. The reduced activities of superoxide dismutase and glutathione peroxidase and increased levels of TBARS were found in brain tissue of the amnesic mice. Melatonin, administered (ig) at doses of 0.1, 1, or 10 mg/kg to the D-galactose-treated mice for 3 months, was sufficient to block these changes. These data suggest that D-galactose is involved in accelerating the brain aging process by elevating free radical generation and reducing antioxidative enzyme activities in vivo. Furthermore, the antioxidative activity of melatonin on the D-galactose-treated mice may account for, at least partially, the improvement of learning and memory function in the aging and amnesic model.