Vitamin E in nature is comprised of a family of tocopherols and tocotrienols. The most studied of these is alpha-tocopherol (alpha-TOH), because this form is retained within the body, and vitamin E deficiency is corrected with this supplement. alpha-TOH is a lipid-soluble antioxidant required for the preservation of cell membranes, and it potentially acts as a defense against oxidative stress. Many studies have investigated the metabolism, transport, and efficacy alpha-TOH in the prevention of sequelae associated with cardiovascular disease (CVD). Supplementation with vitamin E is considered to provide health benefits against CVD through its antioxidant activity, the prevention of lipoprotein oxidation, and the inhibition of platelet aggregation. However, the results from large prospective, randomized, placebo-controlled clinical trials with alpha-TOH have been largely negative. A recent meta-analysis suggests that alpha-TOH supplements may actually increase all-cause mortality; however, the mechanism for this increased risk is unknown. In vitro studies performed in human cell cultures and animal models suggest that vitamin E might increase the hepatic production of cytochrome P450s and MDR1. Induction of CYP3A4 or MDR1 by vitamin E could potentially lower the efficacy of any drug metabolized by CYP3A4 or MDR1. Other possibilities include an adverse effect of alpha-TOH on blood pressure in high-risk populations. Because of the wide popularity and use of vitamin E supplements, further research into potential adverse effects is clearly warranted.