Oxidative stress due to the production of intracellular and extracellular reactive oxygen species may be a major player in the pathogenesis of cardiovascular and other diseases. Because homocysteine and other thiols have pro-oxidant activity, the oxidant stress hypothesis is frequently invoked to explain the damaging effects of homocysteine on vascular cells and tissues. 1, 2 However, the underlying mechanisms of homocysteine-induced vascular injury are still largely unknown in subjects with elevated plasma total homocysteine (tHcy) levels. It is now well established that hyperhomocysteinemia is an independent risk factor for coronary artery disease, cerebrovascular disease, and peripheral vascular occlusive disease, 3–5 yet the question remains: Is homocysteine causal or merely an innocent marker? Several recent studies suggest that mild hyperhomocysteinemia, either basal or transient after a methionine load, can impair endothelial cell function. 6–11 Because antioxidants were effective in blocking endothelial dysfunction during transient hyperhomocysteinemia, it was suggested that oxidative stress was involved in the mechanism. 12–14 Additional support for the oxidative stress hypothesis has come from in vitro studies of cultured endothelial and smooth muscle cells. However, many of these studies used supraphysiological concentrations (1 to 10 mmol/L) of homocysteine under conditions that, in all likelihood, led to the generation of reactive oxygen species in the absence of in vivo antioxidant defense systems.