Vitamin E is the principal lipid-soluble antioxidant in human plasma, and some studies indicate that it may provide cardiovascular protection. To investigate putative mechanisms for vitamin E in this regard, the effect of vitamin E on vascular function and platelet aggregation was examined. In animal models of endothelial dysfunction, vitamin E improved the activity of endothelium-derived nitric oxide, and this effect was not dependent upon the antioxidant protection of LDL. In fact, vitamin E improved endothelial function in part due to the inhibition of protein kinase C (PKC) stimulation. This activity of vitamin E was examined in platelets, and vitamin E inhibited platelet aggregation in part through a mechanism that involves PKC. Moreover, the platelet inhibitory activity of vitamin E was independent of its antioxidant action because platelet inhibition was still observed with isoforms of vitamin E that were devoid of antioxidant activity.