We studied in humans the effect of exogenous secretin in a physiological dose on gastric acid secretion stimulated by pentagastrin and postprandial plasma gastrin concentration. Two doses of pentagastrin, 80 and 160 pmol/kg/hr were used to stimulate gastric acid secretion. Secretin in two doses, 2.8 and 5.6 pmol/kg/hr were tried to study the response on stimulated gastric acid secretion. Intravenous secretin in a dose of 5.6 pmol/kg/hr significantly inhibited the gastric acid output stimulated by intravenous pentagastrin in a dose of 160 pmol/kg/hr, from 11.25±1.5 to 5.99±1.34 meq/hr, while lower dose of intravenous secretin (2.8 pmol/kg/hr) failed to inhibit the gastric acid output stimulated by the same dose of pentagastrin. However, the lower dose of intravenous secretin (2.8 pmol/kg/hr) inhibited the gastric acid output significantly from 8.78±1.21 to 6.37±1.62 meq/hr when gastric secretion was stimulated by the lower dose of pentagastrin (80 pmol/kg/hr). The plasma concentrations of secretin during intravenous secretin in a dose of 2.8 pmol/kg/hr was similar to postprandial plasma concentrations of secretin as previously reported. Doubling the dose of intravenous secretin resulted in almost twofold higher plasma concentrations than postprandial plasma concentrations. In addition, the low dose of secretin (2.8 pmol/kg/hr) suppressed the integrated postprandial gastrin response from 13.9±3.7 to 11.2±2.8 ng/min/ml (P=0.05) when endogenous release of secretin was blocked by intravenous cimetidine. Since the dose of pentagastrin and secretin employed in this study fell in a physiologic range, the inhibitory effect of secretin on stimulated gastric acid secretion appears to be a physiologic action in humans. Contrary to the findings in dogs, the inhibitory action of secretin on gastrin release was not statistically significant but was highly suggestive.