The effect of combining chronic endothelial injury and intermittent meal feeding of a high and low cholesterol, coconut oil, peanut oil diet on plama lipid and lipoprotein content and on the formation of atherosclerotic lesions within the iliac-femoral artery of rabbits was studied. Alternate feeding of a 1 or 0.1% cholesterol, 3% coconut oil, 3% peanut oil diet for 3 to 14 weeks resulted in a 4- to 11-fold increase in plasma cholesterol with 59 to 79% of the plasma cholesterol eluting in a molecular weight fraction comparable to human low density lipoproteins (LDL). In the iliac-femoral artery, an atherosclerotic intimal lesion with an average cross-sectional area of 0.452 mm2 was present in 98% of the animals. The lesion was typically eccentric in location and contained both superficial- and deep-intimal lipid-filled monocyte-macrophages, extracellular lipid, smooth muscle cells, and extracellular connective tissue matrix. The relative percent lipid composition of the iliac-femoral lesion was 62% cholesteryl ester, 21% free cholesterol, and 17% phospholipid. Thus, we conclude that the combination of meal feeding a cholesterol/fat diet, dietary regimen and chronic mild endothelial injury in the rabbit results in (1) a diet-induced hypercholesterolemia in which LDL appear to be the predominant lipoprotein; and (2) a lesion within the iliac-femoral artery comparable in histologic and chemical composition to a human fatty streak.