Decreases in fetal blood pressure stimulate homeostatic stress responses that help return blood pressure to normal levels. Fetal hypothalamus-pituitary-adrenal (HPA) axis responses to hypotension are mediated by chemo- and baroreceptor reflexes and ischemia of the fetal central nervous system. Indomethacin, a nonselective inhibitor of Prostaglandin Endoperoxide Synthase (PGHS)-1 and -2, attenuates the HPA response to hypotension in the fetus. The present study was designed to test the hypothesis that selective inhibition of PGHS-2 also inhibits the HPA response to cerebral hypoperfusion. We studied 13 chronically-catheterized fetal sheep (126- 136 days gestation) Five fetal sheep were subjected to intracerebroventricular infusion of nimesulide (0.1 mg/day), a specific inhibitor of PGHS-2, and 8 were treated with vehicle (DMSO in water) for 5 days. Each fetus was subjected to a 10-min period of brachiocephalic occlusion, which decreased carotid arterial pressure approximately 75% and reflexively increased fetal plasma concentrations of ACTH, POMC, cortisol, and femoral arterial pressure, and decreased fetal heart rate. Nimesulide significantly inhibited the ACTH response to the BCO while significantly augmenting the reflex cardiovascular response and altering fetal heart rate variability consistent with increased sympathetic nervous system activity. The results of this study demonstrate that the activity of PGHS-2 in the brain is a necessary component of the fetal HPA response to cerebral hypoperfusion in the late-gestation fetal sheep. These results are consistent with those of recent study in which we demonstrated that the preparturient increase in fetal ACTH secretion depends upon PGHS-2 activity within the fetal brain.