Although experimental evidence has shown that the neuroprotective effect from estrogen may benefit postmenopausal women, but the clinical use of estrogen was limited by the risk of increasing the cases of mammary and endometrial cancer. This study was designed to evaluate the neuroprotective effects of a novel phytoestrogen alpha-zearalanol (alpha-ZAL), on the cultured rat hippocampal neurons. Following a 24-h exposure of the cells to amyloid beta-peptide fragment 25-35 (A beta 25-35), a significant reduction in cell survival and activities of total superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), as well as increased of malondialdehyde (MDA) were observed. Preincubation of the cells with alpha-ZAL or 17 beta-estradiol(17 beta-E2) prior to A beta 25-35 exposure elevated the cell survival and SOD and GSH-Px activities, and decreased the level of MDA. These data suggested that the phytoestrogen alpha-ZAL, like estrogen, may effectively antagonize A beta 25-35-induced cell toxicity, which might be beneficial for neurons.