Gastric bicarbonate secretion in humans was determined in vivo by using a gastric perfusion-aspiration system. A computer calculated the bicarbonate concentration every 30 s throughout the experiment from measurements of the pH and PCO2 in the aspirate. The total bicarbonate concentration was calculated according to the formula of Henderson and Hasselbalch as the sum of free bicarbonate plus the CO2 that was formed during reaction of bicarbonate with hydrogen ions. In 16 subjects basal gastric bicarbonate secretion was 410 +/- 39 mumol/h (mean +/- SEM). After sham feeding using the chew and spit technique to achieve physiologic vagal activation, the gastric bicarbonate secretion rate increased to 692 +/- 67 mumol/h (p less than 0.001). This response of bicarbonate secretion rate to vagal stimulation was independent of the intragastric pH (range 2-7). In 6 subjects the sham-feeding response was almost abolished (88% inhibition) by the anticholinergic drug benzilonium bromide, however, it was unaffected by premedication with indomethacin. The findings demonstrate that the increase in gastric bicarbonate secretion during the cephalic phase of gastric secretion occurs parallel to the increase in acid secretion. It may therefore be regarded as a physiologic response to reinforce the protective mucus-bicarbonate barrier. The response to vagal stimulation seems to be mediated by a muscarinic transmitter and to be independent of intragastric pH and endogenous prostaglandins.