Aim: To examine whether liquiritigenin, a newly found agonist of selective estrogen receptor-β, has neuroprotective activity against β-amyloid peptide (Aβ) in rat hippocampal neurons. Methods: Primary cultures of rat hippocampal neurons were pretreated with liquiritigenin (0.02, 0.2, and 2 μmol/L) prior to Aβ 25-35 exposure. Following treatment, viability of the cells was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis and by a lactate dehydrogenase activity-based cytotoxicity assay. Intracellular Ca 2+ concentration ([Ca 2+ ] i ) and levels of reactive oxygen species (ROS), as well as apoptotic rates, were determined. Our studies were extended in tests of whether liquiritigenin treatment could inhibit the secretion of Aβ 1-40 as measured using an ELISA method. In order to analyze which genes may be involved, we used a microarray assay to compare gene expression patterns. Finally, the levels of specific proteins related to neurotrophy and neurodenegeration were detected by Western blotting. Results: Pretreated neurons with liquiritigenin in the presence of Aβ 25-35 increased cell viability in a concentration-dependent manner. Liquiritigenin treatment also attenuated Aβ 25-35 -induced increases in [Ca 2+ ] i and ROS level and decreased the apoptotic rate of neurons. Some genes, including B-cell lymphoma/leukemia-2 (Bcl-2), neurotrophin 3 (Ntf-3) and amyloid β (A4) precursor protein-binding, family B, member 1 (Apbb-1) were regulated by liquiritigenin; similar results were shown at the protein level by Western blotting. Conclusion: Our results demonstrate that liquiritigenin exhibits neuroprotective effects against Aβ 25-35 -induced neurotoxicity and that it can decrease the secretion of Aβ 1-40 . Therefore, liquiritigenin may be useful for further study as a prodrug for treatment of Alzheimer's disease.