We studied pentagastrin-stimulated acid and pepsin secretion with three doses (5, 10, and 20 mg) of a new H2-receptor antagonist (famotidine) administered orally to normal male volunteers. A dose response was identified: 2 hr after oral dosing, 5 mg famotidine suppressed stimulated acid secretion to 60% of control and was comparable to 300 mg cimetidine (55% suppression). Higher doses of famotidine yielded significantly more suppression of acid secretion (10 mg yielding 70% and 20 mg, 90%). Pentagastrin-stimulated acid secretion remained decreased (50% of control) 12 hr after oral dosing with 20 mg famotidine. The reduction in pepsin output paralleled the reduction in acid secretion and was primarily due to a reduction in the volume of secretion and not to a change in pepsin concentration. We calculated the components of gastric secretion (acid from parietal cells) and bicarbonate secretion (from nonparietal cells) and found that the primary effect of the H2-receptor antagonists was a dramatic reduction in parietal cell output without a significant decrease in nonparietal secretion. Famotidine proved to be a potent inhibitor of both the parietal component of gastric acid and pepsin output. Famotidine was significantly more potent than cimetidine; 5 mg of famotidine was comparable to 300 mg of cimetidine.