Background: Increased levels of the most electronegative type of LDL, L5, have been observed in the plasma of patients with metabolic syndrome (MetS) and ST-segment elevation myocardial infarction and can induce endothelial dysfunction. Because men have a higher predisposition to developing coronary artery disease than do premenopausal women, we hypothesized that LDL electronegativity is increased in men and promotes endothelial damage. Methods: L5 levels were compared between middle-aged men and age-matched, premenopausal women with or without MetS. We further studied the effects of gender-influenced LDL electronegativity on aortic cellular senescence and DNA damage in leptin receptor-deficient (db/db) mice by using senescence-associated-beta-galactosidase and gamma H2AX staining, respectively. We also studied the protective effects of 17 beta-estradiol and genistein against electronegative LDL-induced senescence in cultured bovine aortic endothelial cells (BAECs). Results: L5 levels were higher in MetS patients than in healthy subjects (P