Spinal cord injury is frequently associated with local tissue hypoxia. As neuronal cells are susceptible to damage caused by low oxygen levels, hypoxia-induced activation of tissue-protective factors could represent an endogenous mechanism for neuron survival following injury. We studied in vivo, in a rat model of intraspinal axotomy of motoneurons, the cell- and time-dependent regulation of the hypoxia-inducible transcription factors (HIFs), HIF1α and HIF2α, as well as one of their target genes, vascular endothelial growth factor (VEGF). VEGF is a potent hypoxia-regulated angiogenic growth factor with recently discovered neuroprotective and neurotrophic activities. While neither HIF1α, HIF2α, nor VEGF mRNA were detected in noninjured motoneurons, we found a strong induction of HIF1α, but not HIF2α mRNA in axotomized motoneurons. HIF1α expression peaked at about 7 days after injury. Moreover, we found increased VEGF mRNA and protein expression around and within the scar but also within motoneurons, peaking around 3 days after axotomy. In addition, increased survival of cultured motoneurons after treatment with VEGF could also be shown. We conclude that axotomized motoneurons in this model respond to injury by specific induction of HIF1α and VEGF expression that may provide an endogenous mechanism with the potential to promote motoneuron survival after injury.