Intracerebroventricular prostaglandin E2 (PGE2) inhibits stimulated gastric acid secretion; however, the central site of action is unknown. Specific PGE2 binding sites have been localized to the ventromedial hypothalamic nucleus and central amygdala (A). The nuclear accumbens has been shown to play a role in central neurotensin-induced antisecretory effects. These studies tested the hypothesis that microinjections of PGE2 into the ventromedial hypothalamic nucleus, central amygdala, and nuclear accumbens inhibit stimulated gastric acid secretion. The hippocampus served as a cerebral control region. Two days before the experiments, metal cannulas were stereotaxically positioned bilaterally into specific areas of the brain, and metal gastric cannulas were operatively implanted, under nembutal anesthesia, in male 250-g Sprague-Dawley rats. On the experimental day, the rats, fasted for 14 hours, were given saline or PGE2 (0.1–1.0 μg in 0.2 μL/side) through the central cannulas 10 minutes before administering pentagastrin (40 μg/kg SC). Gastric secretion was measured at 30-minute intervals and expressed as acid output, micromoles per hour. Acid output (mean ± SE) in control animals was 161 ± 14 μmol/h. Prostaglandin E2 administration at doses of 0.10, 0.50, and 1.0 μg/side (a) into ventromedial hypothalamic nucleus reduced acid output to 53 ± 11, * 36 ± 10,* and 27 ± 11* μmol/h regularly; (b) into NACB reduced acid output to 157 ± 36, 60 ± 12, * and 38 ± 12* μmol/h; and (c) into A reduced acid output to 144 ± 31, 141 ± 26, and 90 ± 19* μmol/h, respectively (*P < 0.05 by Neuman-Keuls test). Prostaglandin E2 (0.50 μg/side) administration into hippocampus had no significant effect on acid output (134 ± 28 μmol/h). Although central PGE2 administration was associated with hyperthermia, this occurred at lower doses than those required to inhibit acid secretion. Prostaglandin E2 administration into specific brain areas known to have PGE2 receptors, the central amygdala and ventromedial hypothalamic nucleus, and into nuclear accumbens inhibits stimulated gastric acid secretion. These observations suggest that PGE2 may have a physiological role in the central control of gastric acid secretion.