Famotidine, a new, potent, long-acting histamine H2-receptor antagonist was compared with cimetidine and ranitidine in 9 patients with Zollinger-Ellison syndrome. The mean minimum daily requirement of famotidine to control gastric acid hypersecretion was 0.24 g (range 0.08-0.48 g) compared with 2.1 g (range 0.6-3.6 g) for ranitidine and 7.8 g (range 1.2-13.2 g) for cimetidine. Equally potent doses of the three drugs had similar onsets of action, but the duration of action of famotidine was 30% longer than the duration of action of either ranitidine or cimetidine (p less than 0.05). Eight patients were treated for up to 9 mo (mean 6 mo) with good control of gastric acid hypersecretion and with no evidence of biochemical or hematologic toxicity. These studies demonstrate that famotidine is nine times more potent than ranitidine and 32 times more potent than cimetidine, has a longer duration of action than ranitidine or cimetidine, and is both safe and effective in the long-term therapy of Zollinger-Ellison syndrome.