Endothelium was removed from the carotid artery of both rat and rabbit using a 2F balloon catheter. The regrowth of endothelium progressed from either end of the vessels but had stopped after 2 weeks in the rabbit and 6 weeks in the rat. Total outgrowth along the vessel was 3 mm in the rabbit and approximately 10 mm in the rat, and by 12 weeks a large zone of the vessel was still devoid of endothelium. Autoradiographic data showed that 12 weeks after the injury endothelial cell replication was reduced to background values. When these vessels were reinjured with a nylon catheter, endothelial cell replication was initiated and the wound rehealed, but these cells did not progress further into the denuded region. Morphologic examination of arteries 12 weeks after balloon denudation showed that endothelial cells, abutting the luminal smooth muscle cells, were larger and not aligned with flow. The luminal smooth muscle cells formed a loose junction with the leading edge of the endothelium and exhibited an extracellular material on their luminal aspect. These results demonstrate that endothelial regeneration will stop before cellular regrowth is complete and that cell senescence is not responsible. The presence of smooth muscle cells on the luminal surface appears to be related to this inhibition of growth.