Selenium is an essential trace nutrient required for synthesis of selenoproteins such as glutathione peroxidase and thioredoxin reductase, the major forms of selenium in endothelium that have important functions relevant to inflammation and cardiovascular disease. Selenium deficiency is associated with cardiomyopathy and sudden cardiac death in animals and low selenium status is associated with cardiovascular disease in humans. Endothelial dysfunction, measured as impaired flow-mediated vasorelaxation of the brachial artery, is a reliable indicator of future cardiovascular disease risk in healthy individuals. To test whether selenium supplementation affects endothelial function, we conducted a randomized, placebo-controlled trial in healthy men administered 300 micrograms of selenium a day as high-selenium yeast for 48 weeks. Brachial artery responsiveness to transient occlusion was assessed at baseline and after 24 and 48 weeks of supplementation. Supplementation increased selenium concentration by more than half in blood plasma and erythrocytes. However, there was no effect of selenium on arterial diameter or blood flow rate before or after transient occlusion, or on the maximum dilated diameter after administration of nitroglycerin. This study indicates that selenium supplementation is not likely to improve endothelial function or peripheral arterial responsiveness in healthy North American men receiving adequate selenium from their diets.