The potassium-chloride cotransporter KCC2 is the main extruder of Cl- in neurons. Reduction of KCC2 levels disturbs the polarity and amplitude of postsynaptic inhibitory potentials induced by GABA and glycine. Motoneuron axotomy induces KCC2 downregulation, which seems to recover with target reinnervation. Thus, we tested the hypothesis that neurotrophic factors might play an important role in regulating KCC2 levels. In this context, we provided axotomized extraocular motoneurons with VEGF or BDNF to determine whether these factors influence the lesion-induced KCC2 downregulation. Adult rats were unilaterally enucleated to axotomize extraocular motoneurons. In the same surgery, a Gelfoam soaked in either vehicle (PBS + 0.1% BSA), VEGF (1 µg/20 µl) or BDNF (5 µg/20 µl) was implanted in the orbit. Eyelids were then sutured. Animals received either 1 or 2 doses of treatment (7 and 15 days of survival time, respectively). After perfusion, the brainstem was cut, and sections were processed for immunofluorescence against ChAT and KCC2 using confocal microscopy. Axotomy induced a reduction in KCC2 optical density in the neuropil and around the motoneuron soma surface of oculomotor, trochlear and abducens nuclei (except for abducens motoneuron somata) which became more conspicuous by 15 days. Administration of VEGF prevented the decrease in KCC2 induced by axotomy, maintaining KCC2 levels similar to control. By contrast, BDNF administration either maintained or even further reduced the levels of KCC2 in comparison with axotomy alone. The present data demonstrate that VEGF, but not BDNF, prevents the axotomy-induced KCC2 downregulation in motoneurons.