Gastric secretory responses to histamine were investigated in anaesthetized dogs following treatment with oral ranitidine at 5 mg/kg twice daily for 358 weeks, and in isolated gastric mucosae from mice receiving sufotidine 240-280 mg.kg/day for 15 months. In neither study were there any significant differences between the acid secretory dose-response curves to histamine in control and test animals. The antisecretory activity of oral sufotidine (1 mg/kg) against histamine-induced acid secretion in the Heidenhain pouch dog was unaltered by twice daily dosing with sufotidine for 14 days. These studies on the effects of H2-antagonists on histamine-stimulated acid secretion found no evidence for development of direct tolerance at the parietal H2-receptor level.