The prolonged disconnection of nerve from muscle results in the death of motoneurons and permanent paralysis. Because clinical nerve injuries generally involve postbirth motoneurons, there is interest in uncovering factors that may support their survival. A rich history of research dating back to the time of Santiago Ramon y Cajal and Viktor Hamburger supports the inference that there are soluble neurotrophic factors associated with nerve and muscle. However, the endogenous factors normally required for motoneuron survival following nerve injury have eluded identification. Two interrelated hypotheses were tested: (1) administration of insulin-like growth factor-II (IGF-II) can support the survival of postbirth motoneurons, and (2) endogenous IGFs are essential for motoneuron survival following nerve injury. We report that IGF-II locally administered close to the proximal nerve stump prevented the death of motoneurons (estimated by relative numbers of neuronal profiles) which ordinarily follows sciatic nerve transection in neonatal rats. By contrast, anti-IGF antiserum, as well as IGF binding proteins-4 and -6, significantly increased (P < 0.01) motoneuron death. This report shows that IGF-II can support survival, and contains the novel observation that endogenous IGF activity in or near nerves is required for motoneuron survival. Other studies have determined that IGF gene and protein expression are increased in nerve and muscle following sciatic nerve crush, and that IGFs are required for nerve regeneration. Taken together, these data show that IGFs are nerve- and muscle-derived soluble factors that support motoneuron survival as well as nerve regeneration.