Post-menopausal estrogen therapy is associated with a decreased incidence of Alzheimer disease and in vitro models have shown that 17β-estradiol is effective in lowering amyloidogenic processing. To examine the effects of estrogen withdrawal and replacement on amyloid β (Aβ) levels and amyloid β-protein precursor (AβPP) processing in vivo, Swedish mutant AβPP transgenic mice were ovariectomized or sham ovariectomized at four weeks of age and treated with placebo or 17β- or 17α-estradiol pellets, the latter being a weak estrogen receptor agonist. Compared to sham ovariectomized mice, ovariectomy with placebo did not alter Aβ levels; however, the levels of Aβ were decreased by 27% and 38% in mice treated with 17β- and 17α-estradiol, respectively, with no change in AβPP holoprotein. Endogenous and exogenous estrogen both significantly increased the levels of sAβPPα, the secreted form of AβPP. The ratio of Aβ/sAβPPα, a measure of amyloidogenic processing, was reduced in all estrogen-containing groups. The Aβ lowering effect of 17β- and 17α-estradiol was replicated when estrogens were administered at a more physiological dose in the drinking water, or when mice were ovariectomized at three months of age. The increased efficacy of 17α-estradiol versus 17β-estradiol may help to develop safe and effective therapeutics.