Injured adult mammalian axons are unable to regenerate spontaneously in the central nervous tissue. This study investigated in two adult rat models the effects of nerve growth factor (NGF) on the capacity of central primary sensory axons to regenerate back into the spinal cord. Sensory fibers were conditioned by transection of the peripheral nerve 1 week prior to the experiment and identified by anterograde tracing with cholera toxin B subunit injected in the sciatic nerve. In the first model, a predegenerated autologous peripheral nerve graft was implanted as a bridge for the transected sensory fibers into a resection gap in the dorsal columns at the tenth thoracic (T10) spinal cord segment. Vehicle or vehicle with purified mouse or recombinant human NGF was continuously infused for 2 weeks directly into the dorsal column at T9, 3 mm from the rostral border of the nerve graft. With vehicle infusion many ascending sensory axons had grown across the nerve bridge, but essentially none had grown back into the rostral cord. In sharp contrast, NGF promoted the reentry into the denervated dorsal columns of 51% of the sensory axons that had reached the rostral level of the nerve graft. Twenty-six percent had grown 2 mm into the spinal tissue and 10% had reached the NGF-infusion site at 3 mm from the nerve graft. A few fibers were found circling around, but not beyond, the infusion site, perhaps due to the chemoattractant action of NGF. In a second model, the fourth lumbar (L4) dorsal root was crushed 2 mm from its insertion point into the spinal cord and the dorsal roots L2, L3, L5, and L6 were transected. Vehicle or vehicle with purified mouse NGF was infused for 2 weeks directly into the lumbar spinal cord, 2.5 mm rostral to the transition zone of the crushed L4 root. With vehicle, only 6% of the regenerating fibers at the transition zone had crossed the root-spinal cord barrier, but not farther than 0.5 mm into the spinal tissue. With NGF, 18% of the fibers at the transition zone were found at 0.5 mm, 9% at 1.5 mm, and 5% at 2.5 mm (the infusion site) from the transition zone. The present results demonstrate that NGF can promote the regeneration of adult sensory fibers into the otherwise nonpermissive spinal cord white matter.