The synthetic trimethyl prostanoid Ro 22-6923 was studied for its effects on histamine-stimulated gastric acid secretion in Heidenhain pouch dogs. The prostanoid (at a p.o. dose as low as 0.05 mg/kg) produced significant inhibition of gastric acid secretion induced by 12 micrograms/kg/h of histamine for 5 h. A dose of 0.5 mg/kg p.o. produced a significant antisecretory effect within 45 min that lasted for 8.5 h. Cimetidine (5 mg/kg p.o.) produced an inhibitory effect on acid output equivalent to the 0.5-mg/kg dose of Ro 22-6923, but the duration of the cimetidine effect was less than 6 h. Administration of Ro 22-6923 i.v. (0.25 mg/kg) inhibited acid output for longer than 8 h. Against a 25-micrograms/kg/h histamine challenge, Ro 22-6923 (0.5 and 1.0 mg/kg) inhibited acid output to an equal degree but for a longer duration than cimetidine (5 mg/kg). Pepsin output was totally inhibited by 0.5 mg/kg of Ro 22-6923, whereas 5 mg/kg of cimetidine inhibited pepsin output by approximately 60%. Pepsin activity in the gastric juice was reduced by Ro 22-6923 and was increased by cimetidine. Blood flow, as estimated by the aminopyrine clearance technique, was reduced slightly by Ro 22-6923 and cimetidine. However, the ratio of clearance to acid secretory rate increased with both compounds, suggesting a direct effect of Ro 22-6923 and cimetidine on acid secretion at the parietal cell level. The results suggest that Ro 22-6923 may be a useful therapeutic agent for peptic ulcer disease in humans.