In the rhesus monkey (Macaca mulatta), the frequency of pulsatile gonadotropic hormone release is relatively constant in the face of widely varying levels of estradiol (E2) in the peripheral circulation--e.g., in the course of the follicular phase of the menstrual cycle and after ovariectomy. This suggests that modulation of the hypothalamic gonadotropin-releasing hormone (GnRH) "pulse generator" by this steroid is not of major physiological importance. Herein is described the unexpected inhibition or total blockade of the electrical activity of this pulse generator in ovariectomized monkeys by physiological levels of exogenous E2. This inhibition began 2-4.5 hr after the initiation of E2 infusion and was noted 1 to 3 weeks after subcutaneous implantation of E2-containing capsules. Pulse generator activity was also arrested during the initiation and subsequent development of estrogen-induced surges of luteinizing hormone. We propose that this inhibition of hypothalamic GnRH pulse generator activity by E2 in ovariectomized monkeys reflects the absence of an ovarian factor that normally protects this neuronal system from the inhibitory action of estrogen during the menstrual cycle.