Axonal regeneration in the peripheral nervous system requires the comigration of Schwann cells along with or ahead of the growing neurites. The present studies were undertaken to elucidate some of the parameters that influence Schwann cell migration into a nerve wound site. We used a modification of an entubulation repair model with two isolated segments of denervated nerve to show that Schwann cells in vivo can bridge a 10-mm distance in the absence of axons. Two pieces of isolated nerve served as point sources of Schwann cells. A crucial finding was that in order for Schwann cells to bridge this distance both isolated/denervated nerve stumps had to be living. In cases where one nerve stump was frozen Schwann cells were not able to bridge the gap distance, although other cell types made up a tissue bridge between both stumps. We have further shown that as Schwann cells grow into this nerve wound site they stain intensely for the low-affinity NGF receptor p75NGFR. Related in vitro experiments showed that Schwann cells actively migrate on cryostat sections of either intact or previously lesioned sciatic nerve, suggesting that they can grow on either axon-containing or axonless areas of nerve tissue. Contrary to migration on sciatic nerve, although Schwann cells attached and survived on cryostat sections of optic nerve, they did not migrate on this substrate. The results of the present experiments suggest that Schwann cells can respond to specific diffusible and substrate bound signals which influence their migration into a nerve repair site.