In this article we investigate the impact of estrous cycle, ovariectomy, and estrogen replacement on both opioid and nonopioid stress-induced analgesia. Stage of estrous strongly influenced analgesia. Diestrus females exhibited the typical male pattern produced by the analgesia inducing procedures used--strong nonopioid analgesia following 10-20 tailshocks, and strong opioid analgesia following 80-100 tailshocks. In these experiments the nonopioid analgesia was slightly attenuated during estrus, but the opioid analgesia was markedly reduced. The role of estrogen in producing these changes was studied with estrogen replacement in ovariectomized subjects. Ovariectomy only slightly altered nonopioid analgesia but eliminated opioid analgesia, which suggests that some estrogen might be necessary to maintain the integrity of the system(s) underlying opioid analgesia. Estrogen administration restored opioid analgesia, but further estrogen suppressed opioid analgesia, duplicating the estrus pattern. It did not suppress nonopioid analgesia. Opioid analgesia was enhanced 102 hr after estrogen replacement, thus duplicating the diestrus pattern. Estrogen thus appears to be responsible for the impact of estrous cycle on opioid but not on nonopioid analgesia. These results suggest that ovarian hormones may modulate the impact of stressors on endogenous pain inhibition and other stress-responsive systems.