Alpha-tocopherol has been reported to exert an anti-atherogenesis effect. We attempted to clarify the effect of alpha-tocopherol-both as an antioxidant and as a nonantioxidant--on apoptosis induced by oxidized low-density lipoprotein (LDL) or oxysterols. Oxidized LDL and oxysterols induced necrosis and/or apoptosis of vascular endothelial cells. The induction of apoptosis was associated with increased caspase-3 activity and the generation of intracellular reactive oxygen species, both the effects of which were attenuated by alpha-tocopherol. Apoptosis was also decreased by beta-tocopherol or intracellular radical scavengers, but these suppressive effects were less than those of alpha-tocopherol. Neither beta-tocopherol nor the scavengers had pronounced effect on caspase-3 activity, but each of them decreased the generation of reactive oxygen species to the same extent as alpha-tocopherol. Our study suggests that alpha-Toc protects against apoptosis not only by scavenging reactive oxygen species, but also by inhibiting caspase activity, which means that its activity may exceed that of a mere antioxidant.