This study investigated hormones progesterone and estrogen on Alzheimer neuropathology in female 3xTg-AD mice. Abundant evidence suggests that the depletion of the sex steroid hormones estrogen and progesterone at menopause is a significant risk factor for the development of AD in women. Furthermore, prospective and case-control studies have demonstrated that hormone therapy (HT) can reduce the risk of AD in women. Given this background, findings from the Women’s Health Initiative Memory Study (WHIMS) demonstrating a higher incidence of dementia in subjects receiving estrogen based HT in the absence and presence of progestin were unexpected. In this study using gonadally intact female 3xTg-AD mice, AD-like neuropathology was apparent by 3 months of age and progressively increased through age 12 months, a time course that was paralleled by behavioral impairment. Ovariectomy-induced depletion of sex steroid hormones in adult female 3xTg-AD mice significantly increased Aβ accumulation and worsened memory performance. Treatment of ovariectomized 3xTg-AD mice with estrogen, but not progesterone, prevented these effects. When estrogen and progesterone were administered in combination, progesterone blocked the beneficial effect of estrogen on Aβ accumulation but not on behavioral performance. Interestingly, progesterone significantly reduced tau hyperphosphorylation when administered both alone and in combination with estrogen. These results demonstrate that estrogen and progesterone independently and interactively regulate AD-like neuropathology and suggest that an optimized hormone therapy may be useful in reducing the risk of AD in postmenopausal women.