Abstract Background Aging is an independent risk factor for cardiovascular and cerebrovascular disease. To date, little is known about the mechanisms of aging of cerebral arteries and whether the aging gene p66Shc is implicated in it. The present study was designed to assess age-induced vascular dysfunction in cerebral and systemic arteries of wild type (wt) and p66Shc−/− mice. Methods Basilar arteries and size matched second order femoral arteries of 3-month (3M), 6-month (6M) and 2-year old (2Y) mice were studied in wt and p66Shc−/− mice. To assess vascular function, arterial rings mounted in a myograph for isometric tension recordings were exposed to increasing concentrations of acetylcholine and sodium nitroprusside. Reactive oxygen species (ROS) generation was assessed in femoral and basilar arteries using the spin trap 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine. Results In wt mice, endothelial function of the femoral artery was not affected by age unlike in the basilar artery where an age-dependent dysfunction was observed. In p66Shc−/− a similar response was observed in the femoral artery; however, age-dependent endothelial dysfunction of the basilar artery was blunted as compared to wt. Levels of ROS were comparable in the femoral arteries of 3M and 2Y of wt and p66Shc−/− mice. Differently, ROS levels in the basilar artery of wt mice were strongly increased by age unlike in p66Shc−/− mice where they remained comparable irrespective of age. Conclusions Endothelial function in cerebral arteries, but not in size-matched systemic ones, is heavily impaired by aging. This process is paralleled by an increased ROS production and is mediated by the p66Shc gene.