Vascular endothelial growth factor (VEGF) is an angiogenic factor with neurotrophic effects in the peripheral nervous system. To determine if VEGF can also promote the survival of central neurons, we examined its effect on HN33 (mouse hippocampal neuron × neuroblastoma) cells deprived of serum. Serum-deprived HN33 cells expressed VEGFR-2 receptors, which, in the presence of VEGF, interacted with the downstream signaling molecules phosphatidylinositol 3′-kinase and phospho-Akt, as demonstrated by immunoprecipitation and Western blotting. Treatment of serum-deprived HN33 cells with VEGF also stimulated the phosphorylation of IκB-α and nuclear translocation of the transcription factor NF-κB. Withdrawal of serum for 24 h reduced HN33 cell viability by ∼50% in the absence of VEGF, but by only ∼20% in the presence of 100 ng/mL of VEGF. These findings support a neurotrophic role for VEGF in the central nervous system, which may be mediated through VEGFR-2 receptors, the protein kinases phosphatidylinositol 3′-kinase and Akt, and the transcription factor NK-κB. Thus, VEGF, like other neurotrophic factors, could exert protective effects in acute or chronic neurodegenerative disorders.