Extracellular superoxide dismutase (EC-SOD) plays an important role in controlling oxidative stress as well as intercellular signaling. In the current study, we tested the effect of EC-SOD overexpression over the lifespan of a set of mice and their wild-type controls to determine the time scale over which EC-SOD overexpression might attenuate aging-induced memory impairment. Mice with overexpression of EC-SOD and wild-type controls were initially trained on the radial-arm maze as young adults (3-5 months) and then retrained during middle age (12-14 months) and retested in old age at 27 and 30 months. There was little EC-SOD effect during the young adult middle age periods. EC-SOD overexpression prevented the decline in choice accuracy when the mice were 27-30 months of age. The EC-SOD overexpressing mice maintained their performance, while the wild-type mice declined to naïve levels of performance by 30 months of age. Enhancement of EC-SOD activity appears to improve memory performance specifically in aging mice. EC-SOD mimetic treatment during the course of aging may hold promise for aging-induced cognitive impairment.