The role of CD11b⁺myeloid cells in axonal regeneration was assessed using axonal injury models and CD11b-TK^mt-30mice expressing a mutated HSV-1 thymidine kinase (TK) gene regulated by the myeloid-specific CD11b promoter. Continuous delivery of ganciclovir at a sciatic nerve lesion site greatly decreased the number of granulocytes/inflammatory monocytes and macrophages in the distal stump of CD11b-TK^mt-30mice. Axonal regeneration and locomotor function recovery were severely compromised in ganciclovir-treated CD11b-TK^mt-30mice. This was caused by an unsuitable growth environment rather than an altered regeneration capacity of neurons. In absence of CD11b⁺cells, the clearance of inhibitory myelin debris was prevented, neurotrophin synthesis was abolished, and blood vessel formation/maintenance was severely compromised in the sciatic nerve distal stump. Spinal cord-injured axons also failed to regenerate through peripheral nerve grafts in the absence of CD11b⁺cells. Therefore, myeloid cells support axonal regeneration and functional recovery by creating a growth-permissive milieu for injured axons.