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Motoneuron death can occur over several spinal levels following muscle denervation due to disease or trauma. We tested whether co-transplantation of embryonic neurons with one or more neurotrophic factors into peripheral nerve improved axon regeneration, muscle fiber area, reinnervation and function to a greater degree than cell transplantation alone. Sciatic nerves of adult Fischer rats were cut to denervate muscles; 1 week later, embryonic day 14–15 ventral spinal cord cells were transplanted into the tibial nerve stump as the only source of neurons for muscle reinnervation. Factors that promote motoneuron survival (i.e. cardiotrophin-1; fibroblast growth factor-2; glial cell line-derived neurotrophic factor [GDNF]; insulin like growth factor-1 [IGF-1]; leukemia inhibitory factor; and hepatocyte growth factor [HGF]) were added to the transplant individually or in combinations. Inclusion of a single factor with the cells resulted in comparable myelinated axon counts, muscle fiber areas, and evoked electromyographic activity (EMG) to cells alone 10 weeks after transplantation. Only cell transplantation with GDNF, HGF and IGF-1 significantly increased motoneuron survival, myelinated axon counts, muscle reinnervation and evoked EMG compared to cells alone. Thus, immediate application of a specific combination of factors to dissociated embryonic neurons improves survival of motoneurons and the long-term function of reinnervated muscle.