Calcitonin gene-related peptide is a 37-residue peptide recently characterized in central and peripheral nervous system. The pharmacologic or physiologic importance of this peptide is not known. We studied the effect of calcitonin gene-related peptide on exogenously stimulated gastric acid secretion (pentagastrin, histamine, bethanechol, and intracisternal thyrotropin-releasing hormone) in the urethane-anesthetized rat. Calcitonin gene-related peptide (2.6 nmol/kg · h) caused a 63%–78% inhibition of gastric acid secretion with all secretagogues tested. The inhibition of gastric acid response to pentagastrin was dose-dependent (2.6–2630 pmol/kg · h), rapid in onset, quickly reversible upon cessation of calcitonin gene-related peptide infusion, and not modified by acute vagotomy or indomethacin pretreatment. In conscious dogs, gastric fistula acid response to pentagastrin was inhibited in a dose-dependent manner by calcitonin gene-related peptide (2.6–260 pmol/ kg · h). The acid response of the Heidenhain pouch to pentagastrin was also inhibited by calcitonin gene-related peptide (260 pmol/kg · h). These results show that calcitonin gene-related peptide is a potent inhibitor of gastric acid secretion in the rat as well as in the dog. Its inhibitory action could be demonstrated against various stimuli and appears to be independent of prostaglandin or vagal pathways.