It is believed that a major reason for the poor functional recovery after peripheral nerve lesion is collateral branching and regrowth of axons to incorrect muscles. Using a facial nerve injury protocol in rats, we previously identified a novel and clinically feasible approach to combat axonal misguidance – the application of neutralizing antibodies against neurotrophic factors to the injured nerve. Here, we investigated whether reduced collateral branching at the lesion site leads to better functional recovery. Treatment of rats with antibodies against nerve growth factor, brain-derived neurotrophic factor, fibroblast growth factor, insulin-like neurotrophic factor I, ciliary neurotrophic factor or glial cell line-derived neurotrophic factor increased the precision of reinnervation, as evaluated by multiple retrograde labelling of motoneurons, more than two-fold as compared with control animals. However, biometric analysis of vibrissae movements did not show positive effects on functional recovery, suggesting that polyneuronal reinnervation – rather than collateral branching – may be the critical limiting factor. In support of this hypothesis, we found that motor end-plates with morphological signs of multiple innervation were much more frequent in reinnervated muscles of rats that did not recover after injury (51% of all end-plates) than in animals with good functional performance (10%). Because polyneuronal innervation of muscle fibres is activity-dependent and can be manipulated, the present findings raise hopes that clinically feasible and effective therapies could be soon designed and tested.