Ovine or rat corticotropin-releasing factor (CRF) injected intracisternally (0.1-2.1 nmol) equipotently inhibited gastric acid secretion in pylorus-ligated rats. CRF given intracisternally in rats or into the third ventricle in dogs suppressed gastric secretion stimulated by thyrotropin-releasing factor, 2-deoxy-D-glucose, or pentagastrin, whereas the gastric response to histamine was unmodified. Microinfusion of CRF in the the paraventricular nucleus or the ventromedial or lateral hypothalamus suppressed gastric acid concentration and increased the volume of gastric secretion. CRF delivered to the caudate putamen nucleus or the frontal cortex had no effect. Vagotomy, adrenalectomy, cervical cord transection, and ganglionic blockade reversed the inhibitory effect of CRF on gastric acid secretion. In rats, peptide action appears to be independent of prostaglandin pathways or changes in blood levels of gastrin and pituitary-derived substances. In dogs, the release of opioid peptides and vasopressin induced by CRF may contribute in part to mediating the gastric response. These results demonstrate that CRF injected into the cerebrospinal fluid suppressed gastric acid secretion in rats and dogs. The action of CRF appears to be mediated through modulation of the autonomic nervous system.