Our previous studies have demonstrated that phytoestrogen -zearalanol (-ZAL) possesses potential benefits in alleviating cell apoptotic death just like oestrogen. However, the underlying mechanism is not fully understood. This study was designed to test the hypothesis that the neuroprotective effect of -ZAL is mediated by oestrogen receptor (ER) as -ZAL owns the benzene ring structure may interact with ER. The present results showed a significant increase in apoptosis in differentiated PC12 cells after a 24-hr exposure to amyloid -peptide fragment 25-35 (A(25-35)), accompanied by decreasing of bcl-2 expression and increasing bax expression, whereas a pre-treatment with -ZAL ameliorated these changes induced by A(25-35). In addition, the -ZAL-mediated cytoprotection was abrogated by ER antagonist but not by ER antagonist. In summary, these data suggest that -ZAL intervenes against A-induced apoptosis via intersecting bcl-2-bax apoptotic pathway in an ER-sensitive manner.