Vascular endothelial growth factor (VEGF), an angiogenic factor, was found to modulate synaptic plasticity by affecting K⁺ and Ca²⁺ channels and protect neuron from death by depressing glutamatergic transmission. However, whether VEGF also modulates neuronal activity through modulating voltage-gated Na⁺ channels (VGSCs), a main determinant of neuronal excitability, we observed the effects of VEGF on Na⁺ channel properties and function on cultured rat hippocampal neurons through whole-cell patch-clamp recording. We found that VEGF decreased the Na⁺ channel excitability by shifting the voltage-dependence of steady-state inactivation to more hyperpolarized direction, and increasing the time constants of recovery from inactivation without significantly affecting the activation process. The effect of VEGF on Na⁺ channel steady-state inactivation was inhibited by the specific VEGF Flk-1 receptor antagonist SU1498, but was not affected by protein kinase C (PKC)-activator 1-oleoyl-2-acetyl- sn -glycerol (OAG). Furthermore, the inhibition of Na⁺ currents by VEGF was frequency-dependent. In addition, the frequency of neuron firing evoked by current injection was reversibly depressed by VEGF. Therefore, our results suggest a potential role of VGSCs in the modulation of VEGF on neuronal excitability.