Calcitonin gene-related peptide (CGRP) and its messenger ribonucleic acid have been identified in brain regions that participate in the central nervous system regulation of gastrointestinal functions. The purpose of this study was to determine the central nervous system effect of CGRP on gastric acid secretion and to delineate the mechanism(s) of its action. Calcitonin gene-related peptide (1 pmol-1 nmol) injected intracerebroventricularly inhibited gastric acid secretion in awake, freely moving, pylorus-ligated rats and the secretory response after intracerebroventricularly administered thyrotropin-releasing hormone. Calcitonin gene-related peptide (rat) and calcitonin (salmon) inhibited gastric secretion similarly. Calcitonin gene-related peptide given intracerebroventricularly inhibited gastric acid secretion stimulated by pentagastrin, histamine, or bethanecol for 2 h in anesthetized rats. Adrenalectomy or noradrenergic blockade with bretylium tosylate did not affect the gastric inhibitory action of CGRP. After subdiaphragmatic truncal vagotomy, CGRP did not exhibit the inhibitory effect on gastric acid secretion stimulated by pentagastrin. These studies indicate that CGRP injected intracerebroventricularly is a potent inhibitor of gastric acid secretion in the rat. Calcitonin gene-related peptide decreases gastric secretion stimulated centrally by thyrotropin-releasing hormone and peripherally by pentagastrin, histamine, or bethanecol. Inhibition of gastric acid secretion by CGRP is not mediated by the sympathetic nervous system but may depend on intact vagus nerves.