A new model was developed to study endothelial regeneration and the effects of endothelial denudation in large arteries. Complete endothelial loss was produced in a sharply defined, unbranched segment of the rat common carotid artery by brief drying with a gentle stream of air along the lumen of the vessel. Platelets became attached to the denuded surface, but no polymorphonuclear or mononuclear leukocytic adherence or infiltration was observed. Regeneration occurred by the ingrowth, from each end of the denuded segment, of sheets of rapidly dividing endothelial cells. Endothelial replacement was complete by 7 to 10 days after drying. It was also noted that, by 14 days after drying, a striking myointimal thickening developed in the central region of the denuded segment. This central region was the last area to be covered with new endothelium; while still denuded, the region showed edema and signs of cellular proliferation in the innermost medial layer. The myointimal thickening consisted of smooth muscle-like cells in a fibroelastic stroma in the deeper zones, and a layer of rounded, relatively undifferentiated cells in the superficial zones. Progressive regression and condensation of the thickening was observed between 14 days and 3 months. In this model, the clear demarcation and completeness of endothelial denudation in the arterial segment allow study of the over-all process of endothelial replacement, avoiding the confusion imposed by islands of residual endothelium or contributions from branch vessels. The results suggest that the new endothelium in this situation is derived from each end of the segment. In addition, because the method of inducing denudation does not cause significant damage to the underlying media (as shown by the absence of inflammatory cell attachment or infiltration), the model offers a unique opportunity to study the relationship between endothelial loss and changes in the vessel wall. The correlation between the duration of endothelial denudation and the extent of myointimal thickening suggests that sustained insudation of certain, as yet undefined, factors from the lumen may provoke cellular proliferation in the arterial wall. Further investigation of this model should provide information relevant to the pathogenesis of the fibromuscular thickenings of human atherosclerosis.