Objective To study the relationship between extracellular signal-regulated kinases（ERK）phosphorylation and indirect activa-tion of the epidermal growth factor receptor（EGFR）in cultured cerebellar granule neurons induced by homocysteine.Methods We pri-marily cultured 7-day-old CD-1 mouse cerebellar granule neurons for 7 days and treated with different agents（saline,AG1478,Hcy and AG1478＋Hcy）.The phosphorylation of ERK was analyzed by Western blot,and apoptotic rate by flow cytometry.Results Compared with saline and AG1478 groups,the phosphorylation of ERK was increased in Hcy group（P 〈 0.05）.When we pretreated the cells with tyr-phostin AG1478,an inhibitor of EGFR,there was no difference in the activation of ERK compared with the control group.We found obvious neuronal apoptosis when 7-day-old CD-1 mouse cerebellar granule neurons were cultured for 7 days and treated with Hcy for 6 hours,and the apoptosis induced by Hcy was aggravated when the neurons were pretreated with AG1478（P 〈 0.05）.No apoptosis was found in the saline and AG1478 groups.Conclusion The role of Hcy on ERK activation suggests the involvement of an indirect activation process of EGFR,which has neural potentially protective effect.