Hypercholesterolemia was induced in pigs by feeding a chow diet supplemented with 1.5% cholesterol and 19.5% lard for periods up to 12 weeks. The aortic intima from areas of spontaneously differing permeability to proteins, as demarcated by their uptake of Evans blue dye, was examined using light microscopy and both scanning and transmission electron microscopy to describe the earliest detectable changes in intimal morphology induced by the diet. After 2, 4, and 6 weeks of feeding, cholesterol/lardfed pigs demonstrated monocyte adherence to the endothelium in areas of enhanced permeability (blue areas) in 86% of samples examined, as compared to 52% in areas of lesser permeability (white areas) and 17% in control animals. Similarly, the number of monocytes in the intima was higher in blue areas than in adjacent white areas or blue areas from control animals. After 12 weeks of feeding, all blue areas showed intimal monocytes, with fewer seen in white areas. Aortic endothelial cells in hypercholesterolemic pigs were normal in ultrastructural appearance, except they contained more lysosomes and cytoplasmic filaments than those from control animals. No lesions were observed at 2, 4, and 6 weeks, although plasma cholesterol levels were substantially elevated (200-400 mg/dl) at these times. A marked hyper-β-lipoproteinemia was evident from 4 weeks onward, but no elevation of serum triglycerides was evident at any stage. Plasma phospholipid concentrations increased but not in direct proportion to cholesterol levels. At 12 weeks, foam cell lesions were observed in areas of enhanced permeability but not in adjacent areas of normal permeability. Lesion foam cells appeared to be derived from the monocytes which adhered to and penetrated the endothelium at earlier stages, since no intimal involvement, or lipid engorgement, by medial smooth muscle cells was observed.