In 1981, Sullivan suggested that a state of iron depletion (ie, reduced iron stores without anemia) was potentially protective against coronary heart disease (CHD).1 This original “iron hypothesis” was an attempt to explain the known sex difference in cardiovascular (CV) risk and the subsequent loss of the protective effect of female gender with menopause. This initial hypothesis was based in part on the observation that men exhibited an age-dependent increase in the accumulation of iron that was not seen in women until after menopause. This, coupled with the observation that hysterectomy without oophorectomy was associated with an increased CHD risk, supported the concept that a diminution in iron stores was protective against CHD. Basic and clinical data have recently begun to provide plausible explanations for a link between iron and atherosclerosis.2,3 See page 2282 The toxic effect of free iron has been linked to oxidative stress through the Fenton reaction, where Fe2+ oxidizes H2O2 leading to its autooxidation and the generation of hydroxyl radicals4 which in turn initiate lipid peroxidation. In addition, biological forms of iron such as heme have the potential to catalyze other oxidative reactions. For example, heme can initiate the oxidation of isolated LDL in vitro4 and, in contrast to free transition metals, LDL in diluted serum.5 Iron is also essential for the synthesis of enzymes that can play a central role in vascular function and atherosclerosis (eg, eNOS, 5-lipoxygenase, and myeloperoxidase). The amount of free ferrous (Fe2+) iron is normally maintained at a very low level in …