In rats with diet-induced hypercholesterolemia, two concomitant changes began to occur within 1 week and persisted for 1 year: an increase in total plasma cholesterol and an increase in the number of mononuclear cells adhering to the aortic intima (up to values 50 times normal). Adherent cells were approximately 90% monocytes and approximately 10% lymphocytes. Adhesion was focal, with some preference for ostia of aortic branches; it was followed by migration into the subendothelial space. The subendothelial monocytes/macrophages progressively became foam cells, thus giving rise to microscopic "fatty streaks." Ultimately, typical atherosclerotic plaques were formed. Four possible mechanisms of increased cell adhesion are suggested. Endothelial changes were mild; myelin figures arising from the endothelial surface were seen by electron microscopy. Endothelial denudation was never observed, neither in light-microscopic preparations stained with AgNO3 nor by ultrastructure. Platelet participation was minimal. It is concluded that in this model atherosclerotic plaques are initiated by mononuclear cell adhesion and emigration; endothelial denudation is not a necessary step in their pathogenesis.