AbstractNeurotrophic factors that support neuronal survival are implicated in axonal regeneration after injury. Specifically, a strong role for BDNF in motor axonal regeneration has been suggested based on its pattern of expression after injury, as well as the expression of its receptors, trkB and p75. Despite considerable in vitro evidence, which demonstrate specific and distinct physiological responses elicited following trkB and p75 activation, relatively little is known about the function of these receptors in vivo. To investigate the roles of the trkB and p75 receptors in motor axonal regeneration, we have used a tibial (TIB)‐ common peroneal (CP) cross suture paradigm in p75 homozygous (−/−) knockout mice, trkB heterozygous (+/−) knockout mice, as well as in their wild‐type controls. Contralateral intact TIB motoneurons, and axotomized TIB motoneurons that regenerated their axons 10 mm into the CP distal nerve stump were identified by fluorescent retrograde tracers and counted in the T11‐L1 spinal segments. Regeneration was evaluated 2, 3, 4, 6, and 8 weeks after nerve repair. Compared to wild‐type animals, there are significantly fewer intact TIB motoneurons in p75 (−/−), but not trkB (+/−) mice. The number of motoneurons that regenerated their axons was significantly increased in the p75 (−/−) knockout mice, but significantly attenuated in the trkB (+/−) mice compared to wild‐type controls. These results suggest that p75 is important for motoneuronal survival during development, but p75 expression after injury serves to inhibit motor axonal regeneration. In addition, full expression of trkB is critical for complete axonal regeneration to proceed. © 2001 John Wiley & Sons, Inc. J Neurobiol 49: 314–325, 2001