Both in mice and humans, low expression levels of vascular endothelial growth factor (VEGF) are linked to adult-onset motor neuron disease or amyotrophic lateral sclerosis (ALS). The mechanism through which reduced VEGF levels result in this phenotype is unknown. We therefore examined the direct effects of VEGF on motor neurons and found VEGF to have a direct neurotrophic effect on motor neurons in vitro. Survival and vulnerability to excitotoxicity of motor neurons from VEGF(delta/delta) mice was however similar to that of motor neurons from non-transgenic littermates. The VEGF concentration in the spinal cord of mutant (G93A) SOD1 mice was not different from that found in wild-type SOD1 overexpressing mice. Upregulation of VEGF in the spinal cord, by housing mutant (G93A) SOD1 mice in hypoxic conditions, did not affect their life span. Our results show that VEGF is a neurotrophic factor for motor neurons in vitro, and shortage of this neurotrophic factor may contribute to the motor neuron death observed in humans and animals with low VEGF expression levels.