To better understand the morphogenesis of atherosclerotic plaque, we evaluated temporal distribution of leukocytes, macrophages, foam cells, vascular smooth muscle cells, and subendothelial lipid in Watanabe heritable hyperlipedimic (WHHL) rabbit aortas. Aortas of WHHL (n=20) and New Zealand White (NZW, controls; n=8) rabbits were perfusion fixed at 1, 3, 6, and 12 months of age. At initial gross evaluation of lipid distribution, we identified aortic areas at high risk for lesion development. In WHHL rabbits, the lipid-positive portion of high-risk areas increased from 3% at 1 month to 50% at 12 months; during the same period, adherent cell count increased from <1 leukocyte and monocyte/mm(2) to 25 leukocytes, 44 monocytes, and 10 foam cells/mm(2). Controls showed no increase over time in lipid-positive areas or cellular adherence to the endothelium. One-month-old WHHL rabbit aortas had scattered lipid-positive cells in the intima (primarily branch points). Immunostaining of these areas did not show rabbit macrophages (RAM antibody) but were actin positive. Occasionally, platelets and monocytes adhered to the endothelial surface. By age 3 months, well-defined fatty streaks/atherosclerotic plaques had RAM-positive cells within foam cell core, along core margins, and in focal clusters in the fibrous cap and subendothelium. By age 12 months, isolated RAM-positive cells were on the endothelial surface, and surface morphology showed endothelial cell disruption foci containing clusters of macrophages and foam cells. Our results indicate that lipid accumulation (extra- and intracellular) is important in the early development of atherosclerotic lesions; a corresponding, slower accumulation of adherent cells on the lesion surface promotes lipid conversion from fatty streak to plaque.