AbstractPeripheral nerve transection or crush induces expression of class 3 semaphorins by epineurial and perineurial cells at the injury site and of the neuropilins neuropilin‐1 and neuropilin‐2 by Schwann and perineurial cells in the nerve segment distal to the injury. Neuropilin‐dependent class 3 semaphorin signaling guides axons during neural development, but the significance of this signaling system for regeneration of adult peripheral nerves is not known. To test the hypothesis that neuropilin‐2 facilitates peripheral‐nerve axonal regeneration, we crushed sciatic nerves of adult neuropilin‐2‐deficient and littermate control mice. Axonal regeneration through the crush site and into the distal nerve segment, repression by the regenerating axons of Schwann cell p75 neurotrophin receptor expression, remyelination of the regenerating axons, and recovery of normal gait were all significantly slower in the neuropilin‐2‐deficient mice than in the control mice. Thus, neuropilin‐2 facilitates peripheral‐nerve axonal regeneration. © 2008 Wiley‐Liss, Inc.