Pituitary adenylate cyclase-activating polypeptide (PACAP) is a new VIP-like blain-gut peptide. Its effects on the motility and secretory functions of the gastrointestinal system have been shown in previous studies. In this study we investigated the effect of intravenous PACAP on gastric acid secretion in conscious pylorus-ligated rats and in gastric fistula rats. PACAP showed significant inhibitory effects on pentagastrin- and histamine-stimulated gastric acid secretion, but no effect on basal or carbachol-stimulated secretion in pylorus-ligated rats. It did show dose-related inhibitory effects both on basal gastric acid secretion and on secretion stimulated by pentagastrin, histamine, or carbachol in gastric fistula rats. PACAP did not alter serum gastrin levels. Inhibition of prostaglandin synthesis with indomethacin and immunoneutralization of somatostatin with anti-somatostatin serum did not prevent the inhibitory effect of PACAP on gastric acid secretion in pylorus-ligated rats. We conclude that PACAP most likely has a direct effect on parietal cells and that this effect may be mediated, at least partially, by inhibition of the action of histamine on parietal cells.