Neuronal excitotoxic death results from excess stimulation by elevated levels of extracellular glutamate acting on N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. While excitotoxicity is typically attenuated by using glutamate receptor antagonists, we report here that neuronal deaths induced directly by brief exposures to glutamate or NMDA were both attenuated by preincubation with platelet-derived growth factor-BB (PDGF-BB). The neuroprotection was concentration and time dependent; preincubation for at least 24 h with a minimum of 10 ng/mL of PDGF-BB was required for maximal neuroprotective effect. The NMDA receptor antagonist MK-801 also afforded partial protection, and when MK-801 was used with PDGF-BB, neuronal survival was comparable to that of untreated controls. When protection of inhibitory and excitatory neurons by PDGF treatment was compared, the excitatory neurons appeared to be selectively protected. The present results demonstrate that PDGF pretreatment can protect neurons from direct glutamate-induced excitotoxicity in vitro and suggests that PDGF might possibly function as a neuroprotective agent in potential therapeutic applications.