The effect of ciliary neurotrophic factor (CNTF) on peripheral nerve regeneration was studied in 6-week-old rats following sciatic nerve transection and juxtaposition of proximal and distal stumps. Rats received intraperitoneal recombinant human CNTF, 1 mg/kg every other day for 12 days. In all CNTF-treated animals, the distribution of the anterograde transport of [3H]leucine-labeled material within the distal stump showed a distinct peak activity 21-24 mm distal to the nerve transection site. In contrast, the radioactivity in control nerves declined rapidly, distributed as proximodistal gradient without a distinct peak. In addition, the amount of radioactivity returning from the growing axon tips in CNTF was significantly greater than controls. The correlative morphologic studies showed a well-advanced stage of myelination in regenerating axons in CNTF compared to controls. These combined in vivo correlative kinetic and morphological studies indicate that CNTF dramatically potentiates axonal regeneration by promoting a greater number of elongating axon tips into the distal stump.