AbstractMidkine (MK) is a growth factor implicated in the development and repair of various tissues, especially neural tissues. MK acts as a reparative neurotrophic factor in damaged peripheral nerves. A postulated role of MK in the degeneration and regeneration of sciatic nerves was explored by comparing wild‐type (Mdk+/+) mice with MK‐deficient (Mdk−/−) mice after freezing injury. In the Mdk−/− mice, a regenerative delay was observed, preceded by a decelerated Wallerian degeneration (WD). The relative wet weight of the soleus muscle slowly declined, and recovery was delayed compared with that in the Mdk+/+ mice. In the regenerating nerve, unmyelinated axons were unevenly distributed, and some axons contained myelin‐like, concentrically lamellated bodies. In the endplates of soleus muscles, nerve terminals containing synaptic vesicles disappeared in both mice. In Mdk−/− mice, the appearance of nerve terminals was delayed in synaptic vesicles of terminal buttons after injury. The recovery of evoked electromyogram was delayed in Mdk−/− mice compared with Mdk+/+ mice. Our results suggested a delay in axonal degeneration and regeneration in Mdk−/− mice compared with Mdk+/+ mice, and the delayed regeneration was associated with a delayed recovery of motor function. These findings show that a lack of MK following peripheral nerve injury is a critical factor in degeneration and regeneration, and manipulation of the supply of MK may offer interesting therapeutic options for the treatment of peripheral nerve damage. © 2009 Wiley‐Liss, Inc.