A slow rate of nerve regeneration conspires together with atrophy and degeneration of denervated organs to increase the risk of permanent disability following injury to the mammalian peripheral nervous system. Therefore, it is of both practical and theoretical interest to identify those endogenous factors that determine the spontaneous velocity of nerve regeneration, and to discover exogenous factors which hold promise for augmenting the rate. We report that locally infused insulin-like growth factor II significantly increases the speed of sensory axon regeneration in rat sciatic nerves. It appeared that 1 microgram/ml insulin-like growth factor II acted through insulin-like growth factor receptors, because a comparable concentration of insulin had little effect. Furthermore, there was a sustained reduction in regeneration rate when an anti-insulin-like growth factor II antiserum was continuously infused near a window in the epineurium located just below a site of nerve crush, indicating that the spontaneous regeneration rate was continuously dependent on endogenous insulin-like growth factor activity. These results show that exogenously administered insulin-like growth factor II can increase the rate of peripheral nerve regeneration, and that the endogenous insulin-like growth factors in nerves are required to maintain the normal rate of regeneration. These in vivo data complement previous observations showing that insulin-like growth factors can increase neurite outgrowth in cultured neurons, and that insulin-like growth factor II gene expression is correlated with synapse development. They further support the hypothesis that insulin-like growth factors play a role in nerve regeneration.