Rabbits have been extensively used in the past for experimental production of arterial lesions by simple short-term cholesterol feeding. However, most lesions thus produced have been composed principally of foam cells and have seldom developed necrosis and complications such as calcification, ulceration, and thrombosis, in sharp contrast to human atherosclerotic lesions. Some recent experiments have indicated that by introducing certain types of dietary regimen non-necrotic proliferative arterial lesions and also necrotic intimal lesions strikingly similar to human atheroma can be produced in rabbits. However, the necrotic lesions were presumably transformed from foam cell lesions and the sequence of events does not appear to have been precisely the same as in man. The current study was carried out in an attempt to (1) produce by dietary means atherosclerotic lesions in rabbits with a pathogenetic sequence of events more closely approximating those in man, and (2) study by electron microscopy changes that might occur in architectural arrangement and subcellular components of smooth muscle cells of the inner media and of the intimal masses in the early stages of atherosclerosis. By feeding rabbits high fat-cholesterol diets, non-necrotic, and necrotic atherosclerotic lesions closely resembling human atheroclerosis have been produced within 12 weeks. The most prominent feature of non-necrotic lesions produced was the smooth muscle cells in either the mature or immature form or in any stage of maturity between the two extremes. Smooth muscle cells containing a large amount of lipid and macrophages containing variable amounts of fat were far more common in rabbit lesions than in most human lesions. In man non-necrotic atherosclerotic lesions consisting largely of smooth muscle cells appear to progress to necrotic atherosclerotic lesions. In the current study this occurred in only one rabbit, probably because of the short duration of experiments. In the atherosclerotic lesions of these rabbits cells that appear to be extremely active exist side by side with cells appearing much less active, which may even contain degenerative elements. The direct effect of the diet may be to depress and damage smooth muscle cells of the vessel wall with the “active cells” appearing as a secondary phenomenon in response to products released by injured cells. Another possibility is that the direct effect of the diet is to stimulate the metabolism of smooth muscle cells of the intima with damage of some occurring as a result of excessive stimulation. Other explanations are also possible but all must take into account the metabolism of smooth muscle cells of inner media and intima. In both man and rabbits changes in the internal elastica and the inner media appear concomitantly with intimal changes. The changes in the internal elastica include widening of the fenestrae making the intima and inner media essentially one unit in many areas. Changes in the smooth muscle cell of the inner media parallel those of the smooth muscle cell in the intima and include distention with lipid and appearance of fibroblast-like smooth muscle cells. Many smooth muscle cells actually lie within the fenestrae of the internal elastica leading to a speculation that smooth muscle cells migrate between the inner media and intima, perhaps in both directions. The essence of the pathogenesis of atherosclerosis in both man and rabbits would appear to be the direct or indirect response of smooth muscle cells in the intima and inner media to excess lipids. Difference in response between rabbits and man seem to be largely a matter of degree. Qualitative differences in response of the arterial wall due to species specificity may be present but there is little or no evidence to support this idea. With the information available the rabbit would appear to be as suitable for the study of certain fundamental aspects of atherosclerosis as any other mammal in spite of the fact that he is primarily a herbivore.