Estrogen is beneficial to patients with Alzheimer's disease (AD) but has a limited clinical use due to its proliferative and oncogenic effects on non-neuronal cells responsive to estrogen. In an attempt to find an estrogen substitute that retains the beneficial effects of estrogen with minimal side effects, we compared the neuroprotective and proliferative effects of genistein, a selective estrogen receptor (ER) beta-agonist, with those of estrogen. Genistein and 17beta-estradiol showed comparable levels of protection against Abeta-induced deaths of cultured SH-SY5Y human neuroblastoma cells, which were blocked by an estrogen receptor antagonist, ICI 182,780. On the other hand, 17beta-estradiol, but not genistein, induced proliferation of uterine endometrial cells. Our results suggest that genistein is a potential alternative to estrogen in the treatment of Alzheimer's disease.