Oxidative stress is a continuous level of oxidative damage in animal cells, which is caused by an overabundance of reactive oxygen species or a decline in antioxidant ability against them. Oxidative stress increases with individual risk factors of atherosclerosis such as obesity, hypertension, hyperlipidemia, diabetes and smoking. Thus, oxidative stress is considered to play a key role in the pathogenesis of atherosclerosis. This review discusses the relationship between oxidative stress and atherosclerosis based on findings from our research group. We have found that atherosclerotic lesions are formed in the aorta of mice fed a high-cholesterol and high-linoleic diet, in parallel with elevated serum lipid peroxide levels. This model is useful for primary screening of antiatherosclerotic agents with antioxidative activity. One notable factor in the development of atherosclerosis is oxidized low-density lipoprotein (OxLDL). In order to examine OxLDL levels in blood, we have developed anion-exchange HPLC methods using stepwise elution. Using these methods, we have found that OxLDL markedly increases in a rat model of metabolic syndrome, in animals exposed to cigarette smoke and in smokers in parallel with other oxidative stress markers. These oxidative stress markers have been attenuated by administration of several antioxidants. In addition, we have found that smoking accelerates atherogenesis in the aorta of apoE-deficient mice and this acceleration can be ameliorated by administration of vitamin E. These observations suggest that antioxidant supplementation may be an effective therapeutic strategy for metabolic syndrome and smoking-induced diseases in which elevated oxidative stress plays a pivotal role.