The transcriptional factor Sox2 and epidermal growth factor receptor (Egfr)-mediated signaling are both required for self-renewal of neural precursor cells (NPCs). However, the mechanism by which these factors coordinately regulate this process is largely unknown. Here we show that Egfr-mediated signaling promotes Sox2 expression, which in turn binds to the Egfr promoter and directly upregulates Egfr expression. Knockdown of Sox2 by RNA interference downregulates Egfr expression and attenuates colony formation of NPCs, whereas overexpression of Sox2 elevates Egfr expression and promotes NPC self-renewal. Moreover, the effect of Sox2 on NPC self-renewal is completely inhibited by AG1478, a specific inhibitor for Egfr; it is also inhibited by LY294002 and U0126, selective antagonists for phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (Erk1/2), respectively. Collectively, we conclude that NPC self-renewal is enhanced through a novel cellular feedback loop with mutual regulation of Egfr and Sox2.