A large percentage of vascular reconstructions, endarterectomies, and angioplasties fail postoperatively due to thrombosis and restenosis. Many of these failures are thought to result from an inability of the vascular endothelium to adequately regenerate and cover the denuded area. After balloon catheter denudation of the rat carotid artery, regrowth of endothelium ceases after approximately 6 wk, leaving a large area devoid of endothelium. Here we show that this cessation of reendothelialization can be overcome by the systemic administration of basic fibroblast growth factor (bFGF). Administration of 120 micrograms bFGF over an 8-h period caused a highly significant increase in the replication rate of endothelial cells at the leading edge of 38.5 vs. 2.1% in controls, and, when given over a longer period of time (12 micrograms daily for 12 d), resulted in a significant increase in the extent of endothelial outgrowth onto the denuded surface. Furthermore, total regrowth could be achieved within 10 wk after balloon catheter denudation when 12 micrograms bFGF was injected twice per week for a period of 8 wk. Endothelium in unmanipulated arteries responded to bFGF with a significant increase in replication, but no increase in endothelial cell density was observed in these arteries. These data demonstrate that bFGF can act as a potent mitogen for vascular endothelial cells in vivo, and add considerably to our understanding of the mechanism underlying endothelial repair after in vivo vascular injuries.