Atherosclerotic cardiovascular disease (CVD) and diabetic vascular disease have been associated with an increase in oxidative stress. Mechanistic studies in vitro and in animals have demonstrated a direct role for oxidatively modified protein and lipid molecules in the pathophysiology of these diseases. As a result of this oxidation hypothesis numerous studies have been carried out over the past 5-10 years testing the ability of antioxidant vitamins to decrease the incidence of these diseases. The general consensus from these studies, involving over 200,000 individuals, has been that antioxidant vitamins do not provide any vascular protection. Moreover, several of these studies have demonstrated that antioxidant supplementation may be associated with an increased incidence of disease and mortality. One reason why these antioxidant vitamins may have failed to demonstrate benefit may have been due to inappropriate patient selection. In this review we provide supporting clinical evidence and a mechanistic basis for utilizing a genetic marker, the haptoglobin (Hp) genotype, in determining whether antioxidant vitamin therapy may or may not be beneficial for a given patient with diabetes.