Vascular endothelial growth factor (VEGF) delays disease onset and progression in transgenic rodent models of familial amyotrophic lateral sclerosis (ALS). Because most cases of ALS are sporadic, it is important to determine whether VEGF can protect motoneurons in a nontransgenic ALS paradigm. We tested this possibility in a new model of chronic excitotoxic spinal neurodegeneration in the rat. Using osmotic minipumps, we continuously infused the glutamate receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) directly in the lumbar spinal cord. The effect of this treatment on motor behavior was assessed with 3 motor performance tests, and neurodegeneration was evaluated by histologic and immunohistochemical analyses. AMPA infusion produced dose-dependent progressive hindlimb motor deficits, reaching complete bilateral paralysis in approximately 10 days, which was correlated with the loss of spinal motoneurons. VEGF administered together with AMPA completely prevented the motor deficits, and the motoneuron death was reduced by more than 75%. Thus, we have developed an in vivo model of progressive spinal motoneuron death due to overactivation of AMPA receptors. The finding that VEGF protected motoneurons from this AMPA receptor-mediated excitotoxic death suggests that it may be a therapeutic agent in sporadic ALS.