In addition to epidemiologic studies suggesting a benefit for high intakes of alpha-tocopherol, studies following supplementation in humans have clearly shown that alpha-tocopherol decreases lipid peroxidation, platelet aggregation, and functions as a potent anti-inflammatory agent. However, prospective human clinical trials with alpha-tocopherol alone and in combination with other antioxidants have been largely negative. In this review, we critically appraise the various clinical trials and provide recommendations for future research.