Oxytocin (OXY) is a nonapeptide of hypothalamic origin which has defined roles in the female reproductive functions of lactation and labor. However, OXY may have other physiological functions because of its presence in the male and its release in response to stress. Available evidence suggests prostaglandins may stimulate the release of OXY. These experiments sought to determine if the stressors, endotoxin and hemorrhage, would release OXY in the chronically catheterized, freely behaving male rat and what effect the antipyretic and prostaglandin synthesis inhibiting drug, indomethacin, would have on these responses. Endotoxin caused a marked release of OXY from mean baseline levels of 5 pg/ml to mean peak levels of 168 pg/ml. Indomethacin greatly attenuated this increase. In contrast, OXY release in response to hemorrhage of either 22 or 44%of the blood volume of the rat was enhanced by indomethacin. Indomethacin increased the hemorrhage-induced OXY levels about 2-fold over a 2-hour posthemorrhage period. Indomethacin alone had no effect on OXY levels. These data verify that stress is a potent stimulus for OXY release and strengthen the hypothesis that prostaglandins mediate OXY release. The paradoxical effects of indomethacin on OXY release suggest that the prostaglandins may have different effects on OXY release depending upon the evoking stimulus.