Our previous studies have demonstrated that phytoestrogen alpha-zearalanol (alpha-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 alpha-ZAL is mediated by oestrogen receptor (ER) as alpha-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 beta-peptide fragment 25-35 (Abeta25-35), accompanied by decreasing of bcl-2 expression and increasing bax expression, whereas a pre-treatment with alpha-ZAL ameliorated these changes induced by Abeta25-35. In addition, the alpha-ZAL-mediated cytoprotection was abrogated by ERalpha antagonist but not by ERbeta antagonist. In summary, these data suggest that alpha-ZAL intervenes against Abeta-induced apoptosis via intersecting bcl-2-bax apoptotic pathway in an ERalpha-sensitive manner.