Fifteen long-lived and fifteen young healthy subjects were enrolled in this study to verify the involvement of age-associated oxidative challenge in the mechanisms that control platelet activation. Our results showed in old subjects an enhancement of ex vivo platelet responsiveness to ADP and collagen, measured both in whole blood and in platelet rich plasma, an increased cytosolic calcium content, a decreased membrane fluidity and a lower intraplatelet nitrate/nitrite (NO(x)) amount. Additionally, an increased plasma content of peroxidative by-products (TBARS) and a decreased antioxidant plasma capacity together with a reduced lag time for in vitro oxidation of low density lipoprotein (LDL) and a diminished plasma NO(x) bioavailability were observed in aged subjects. Lag time for LDL oxidation was negatively correlated with plasma TBARS level, and positively correlated with intraplatelet NO(x) content. Findings of this study may support the speculation that advancing age increases the susceptibility of LDL to oxidative modifications and favors platelet activation by oxidized LDL-induced decrease of nitric oxide bioactivity.