The selective estrogen receptor modulator, tamoxifen, effectively slows the progression of estrogen-positive breast cancer and reduces the possibility of this cancer developing in women at high risk. Despite the widespread acceptance of tamoxifen as a therapeutic agent for this disease, its effects on other estrogen-dependent pathways, particularly on neural circuits regulating brain function and peripheral hormone secretion, are poorly understood. The present study, using previously ovariectomized rhesus monkeys, examined the effects of tamoxifen, in both the presence and absence of estradiol replacement, on the reproductive and hypo-thalamic-pituitary-adrenal (HPA) axes. In Experiment 1, monkeys randomly assigned to three groups (n = 8 each) were treated with placebo and either two doses of estradiol, two doses of tamoxifen alone, or two doses of tamoxifen plus high-dose estradiol to assess the effects on negative feedback suppression of luteinizing hormone (LH). Both doses of tamoxifen effectively antagonized the negative feedback efficacy of estradiol on LH secretion. In contrast, neither the low- or high-dose tamoxifen alone had any effect on LH secretion, as concentrations during tamoxifen treatments were indistinguishable from those during placebo. In Experiment 2, females were randomly assigned to one of four treatment groups (placebo, n = 6; estradiol, n = 5; tamoxifen only, n = 5; or tamoxifen plus estradiol, n = 6) to assess the effects on glucocorticoid negative feedback and pituitary and adrenal responsiveness to exogenous corticotropin- releasing hormone (CRH). Tamoxifen also antagonized the facilitating effects of estradiol on basal and CRH-induced ACTH and cortisol secretion. However, this antagonism produced basal and CRH-stimulated cortisol and ACTH concentrations that were lower than placebo-treated females. Interestingly, tamoxifen in the absence of estradiol produced a similar diminution in ACTH and cortisol response. These data suggest that, in the presence of estradiol, tamoxifen not only antagonized estrogenic facilitation of HPA responsivity but also actually attenuated the response compared with the placebo-treatment condition. Taken together, these data indicate that tamoxifen acts as an estrogen antagonist on the neural circuits controlling the neuroendocrine regulation of the hypothalamic-pituitary-ovarian and adrenal axes in ovariectomized macaque females.