We have investigated the possible roles of NGF, and of impulse activity, in the regeneration of sensory nerves. Unexpectedly, the ability of crushed axons to regrow and to restore functional recovery of three sensory modalities in adult rat skin (A alpha-mediated touch, A delta-mediated mechanonociception, and C-fiber-mediated heat nociception) was totally unaffected by anti-NGF treatment. This finding applied even when the anti-NGF dosage was almost eight times that which entirely blocked collateral sprouting of the undamaged axons of both classes of nociceptive nerves (the A alpha-axons do not sprout in adult animals). In the same anti-NGF-treated animal, regeneration would proceed normally on the one side, while collateral sprouting was prevented on the other. Light microscopic and EM examination revealed that in the denervated skin the regenerating axons utilized the same dermal perineurial pathways followed by collaterally sprouting axons. Regeneration within these antibody-accessible pathways progressed normally during anti-NGF treatment, extending 1-2 cm beyond the former field borders, that is, into territory whose invasion by collaterally sprouting axons was totally blocked. The blood-nerve barrier is absent within the degenerating peripheral nerve trunk, a putative NGF source for regenerating fibers but not for sprouting ones. The NGF-independent regeneration was also found to be unaffected when putative spinal cord sources of NGF were eliminated by dorsal root excision. Anti-NGF treatment also failed to block regeneration across 4 mm excision gaps in the nerve trunk. The daily anti-NGF regime continued to be effective for at least 8 weeks, at which time newly evoked collateral sprouting could still be blocked. Exogenous NGF, in doses that evoke collateral sprouting de novo in normal skin, failed to influence regeneration. Finally, an electrical stimulus regime, which markedly reduces the latency of collateral sprouting, failed to affect the time to arrival of regenerating axons at the skin, or the rate of their arborization in it. We conclude that, in striking contrast to their collateral sprouting, the regeneration of nociceptive axons occurs independently of endogenous NGF and is unaffected by impulse activity. These findings further support the proposal that these two growth behaviors have basically different biological functions in the organism.