Oxidative stress has been implicated in cognitive impairment in both old experimental animals and aged humans. This implication has led to the notion that antioxidant defense mechanisms in the brain are not sufficient to prevent age-related increase in oxidative damage and that dietary intake of a variety of antioxidants might be beneficial for preserving brain function. Here we report a dramatic loss of learning and memory function from 8 to 11 months of age in mice, associated with marked increases in several markers of brain oxidative stress. Chronic systemic administration of two synthetic catalytic scavengers of reactive oxygen species, Eukarion experimental compounds EUK-189 and EUK-207, from 8 to 11 months almost completely reversed cognitive deficits and increase in oxidative stress taking place during this time period in brain. In particular, increase in protein oxidation was completely prevented, whereas increase in lipid peroxidation was decreased by approximately 50%. In addition, we observed a significant negative correlation between contextual fear learning and levels of protein oxidation in brain. These results further support the role of reactive oxygen species in age-related learning impairment and suggest potential clinical applications for synthetic catalytic scavengers of reactive oxygen species.