Advancing age as well as diseases such as diabetes are characterized by both increased large artery stiffness and impaired peripheral artery function. It has been hypothesized that greater large artery stiffness causes peripheral artery dysfunction; however, a cause-and-effect relationship has not previously been established. We used elastin heterozygote mice (Eln+/–) as a model of increased large artery stiffness without co-morbidities unrelated to the large artery properties. Aortic stiffness, measured by pulse wave velocity, was ˜35% greater in Eln+/– mice than in wild-type (Eln+/+) mice (P = 0.04). Endothelium-dependent dilatation (EDD), assessed by the maximal dilatation to acetylcholine, was ˜40% lower in Eln+/– than Eln+/+ mice in the middle cerebral artery (MCA, P < 0.001), but was similar between groups in the gastrocnemius feed arteries (GFA, P = 0.79). In the MCA, EDD did not differ between groups after incubation with the nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine methyl ester (P > 0.05), indicating that lower NO bioavailability contributed to the impaired EDD in Eln+/– mice. Superoxide production and content of the oxidative stress marker nitrotyrosine was higher in MCAs from Eln+/− compared with Eln+/+ mice (P < 0.05). In the MCA, after incubation with the superoxide scavenger TEMPOL, maximal EDD improved by ˜65% in Eln+/– (P = 0.002), but was unchanged in Eln+/+ mice (P = 0.17). These results indicate that greater large artery stiffness has a more profound effect on endothelial function in cerebral arteries compared with skeletal muscle feed arteries. Greater large artery stiffness can cause cerebral artery endothelial dysfunction by reducing NO bioavailability and increasing oxidative stress.