The Metabolic Syndrome is a disease entity characterized by the joint presence of several metabolic and vascular disturbances (hypertension, central obesity, diabetes and dyslipidemia), whose prevalence increases with age, which is very closely related to the development of atherosclerosis. The shortening of telomere length in leukocytes, which is used as a marker of aging, has been associated with the cardiovascular risk factors included in the definition of Metabolic Syndrome, with insulin resistance promoting their shortening. The simultaneous presence of these factors leads to increased oxidative stress mediated by the phagocytic NADPH oxidase, as reflected in the increased levels of oxidative stress marker TBARS, which accelerates the erosion of telomeres primarily through telomeric DNA oxidation. Thus, NADPH oxidase overactivity promotes telomere shortening in Metabolic Syndrome and insulin resistant patients, and increases the risk of vascular complications, as shown by the greater prevalence of several surrogate markers atherothrombotic risk (carotid intima-media thickness and metalloproteinase-9) in these patients. The involvement of the NADPH oxidase in this process is supported by in vitro findings in cultured murine macrophages Finally, our in vivo and in vitro results underline a relevant role for hyperglycemia in the telomere shortening by promoting NADPH oxidase-dependent oxidative stress.