Although increased vascular stiffness is more prominent in aging males than females, and males are more prone to vascular disease with aging, no study has investigated the genes potentially responsible for sex differences in vascular aging. We tested the hypothesis that the transcriptional adaptation to aging differs in males and females using a monkey model, which is not only physiologically and phylogenetically closer to humans than the more commonly studied rodent models but also is not afflicted with the most common forms of vascular disease that accompany the aging process in humans, e.g., atherosclerosis, hypertension, and diabetes. The transcriptional profile of the aorta was compared by high-density microarrays between young and old males or females (n = 6/group). About 600 genes were expressed differentially when comparing old versus young animals. Surprisingly, <5% of these genes were shared between males and females. Radical differences between sexes were especially apparent for genes regulating the extracellular matrix, which relates to stiffness. Aging males were also more prone than females to genes switching smooth muscle cells from the "contractile" to "secretory" phenotype. Other sex differences involved genes participating in DNA repair, stress response, and cell signaling. Therefore, major differences of gene regulation exist between males and females in vascular aging, which may underlie the physiological differences characterizing aging arteries in males and females. Furthermore, the analyses in young monkeys demonstrated differences in genes regulating vascular structure, implying that the sex differences in vascular stiffness that develop with aging are programmed at an early age.