Depletion of estrogens and progesterone at menopause has been linked to an increased risk for the development of Alzheimer's disease (AD) in women. A currently controversial literature indicates that although treatment of postmenopausal women with hormone therapy (HT) may reduce the risk of AD, several parameters of HT may limit its potential efficacy and perhaps, even exacerbate AD risk. One such parameter is continuous vs. cyclic delivery of the progestogen component of HT. Recent experimental evidence suggests that continuous progesterone can attenuate neural actions of estradiol (E(2)). In the present study, we compared the effects of continuous and cyclic progesterone treatment in the presence and absence of E(2) in ovariectomized 3xTg-AD mice, a transgenic mouse model of AD. We found that ovariectomy-induced hormone depletion increases AD-like pathology in female 3xTg-AD mice, including accumulation of beta-amyloid, tau hyperphosphorylation, and impaired hippocampal-dependent behavior. E(2) treatment alone prevents the increases in pathology. Continuous progesterone did not affect beta-amyloid levels when delivered alone but blocked the Abeta-lowering action of E(2). In contrast, cyclic progesterone significantly reduced beta-amyloid levels by itself and enhanced rather than inhibited the E(2) effects. These results provide new insight into the neural interactions between E(2) and progesterone that may prove valuable in optimizing HT regimens in postmenopausal women.