1. The canine gastric arterial supply was isolated and perfused by means of an extracorporeal circuit. The gastric venous blood was returned to the dog's venous system. Histamine acid phosphate (20 microgram min-1) infused intra-arterially gave a mean peak acid output of 2.3 m-mole per 10 min. 2. When a plateau of acid secretion was observed, the gastric venous blood was diverted to the oxygenator, by-passing the dog entirely (vascular isolation). This resulted in an immediate decrease in acid output which fell to or near zero by 90 min after isolation. 3. In three dogs, part of a lung was perfused in series with the stomach before total isolation of the gastric vasculature. With histamine stimulation, acid secretion was observed for about 1 hr with a peak acid output of 0.5 m-mole per 10 min during the period of total isolation. 4. Indomethacin (10 mg kg-1) was given to five dogs approximately 1 hr before vascular isolation. After acid secretion reached a plateau (mean peak acid output 2.3 m-mole per 10 minutes), the gastric circulation was isolated by diverting the gastric venous blood to the oxygenator. Acid secretion was maintained for 50 min, after which it gradually declined to reach 30% of the peak value after 2 hr. 5. Indomethacin (10 mg kg-1) and methysergide bimaleate (1 mg) were given I.V. to five dogs approximately 1 hr before vascular isolation. After acid secretion reached a plateau (peak output 3.0 m-mole per 10 min), the gastric circulation was isolated by diverting the gastric venous blood to the oxygenator. The plateau of secretion was maintained for a further 2 hr with no inhibition. 6. Methysergide bimaleate given alone did not prevent the inhibition of secretion caused by the total vascular isolation of the stomach. 7. These results suggest that in the isolated canine stomach preparation naturally occurring inhibitors of gastric acid secretion, which are normally metabolized at least in part in the lungs, accumulate in the circulation and may account for the observed suppression of acid secretion.