Although there is abundant clinical evidence that the consumption of alcohol (ethanol) in moderate amounts has a protective effect on coronary artery disease, the mechanism of this effect is not understood. The prevailing theory supported by a limited number of clinical and experimental animal studies indicates that the ability of alcohol to elevate serum high-density lipoprotein cholesterol levels is an important mechanism. Although there have been a large number of studies on the effects of alcohol on serum lipoprotein and apolipoproteins on coronary artery disease, there have been very few that have, at the same time, looked directly and systematically at its effects on the histopathological development of atherosclerotic lesions. In the following studies we employed the hyperlipidemic C57BL/6 female mouse model and formulated an all liquid high fat atherogenic diet to provide the mice with the 3% or 6% alcohol. After 22 weeks on this diet, alcohol markedly inhibited the development of fatty streak atherosclerotic lesions in a dose-dependent fashion. Surprisingly, there was a dose-dependent decrease in plasma high-density lipoprotein cholesterol values, which suggests that high-density lipoprotein alterations play little or no role in the amelioration of atherosclerosis in this model.