Gastric inhibitory polypeptide (GIP), given to dogs in graded doses (range 0.25-2 micrograms/kg/hr) against a constant background stimulation with pentagastrin (4 micrograms/kg/hr), failed to affect the acid secretion at all doses used except the largest one (2 micrograms/kg/hr) which significantly reduced the acid secretion only from the vagally denervated portion of the stomach (Heidenhain pouch, HP) while raising plasma GIP two to three times above the levels reached with duodenal fat. GIP infused in a constant dose (1 microgram/kg/hr) significantly reduced the HP responses to lower (0.5-2 micrograms/kg/hr) but not to higher (4-16 micrograms/kg/hr) doses of pentagastrin, the kinetics of this inhibition being of competitive type. GIP was ineffective against a constant near maximal stimulation with pentagastrin (4 micrograms/kg/hr), histamine (40 micrograms/kg/hr), or liver extract meal, whereas fat (10 g), given intraduodenally or intravenously, was a powerful inhibitor of acid responses to these stimulants both from the innervated and denervated stomach. Plasma GIP reached similar levels with exogenous GIP and duodenal fat but remained unchanged with intravenous infusion of fat.