To elucidate the mechanism of gastric hypersecretion induced by cysteamine, the effects of atropine, cimetidine, proglumide, cromolyn sodium and tranilast on the cysteamine response were studied in rats. Under urethane anesthesia, rat stomachs were perfused with 4 ml of physiological saline (pH 6.0) every 15 min. Acid secretion was progressively increased by cysteamine HCl (300 mg/kg, s.c.) for the duration of the experiment (6 hr). This effect was completely blocked by cimetidine and partially blocked by proglumide and atropine. Cromolyn sodium and tranilast, inhibitors of histamine release, also blocked cysteamine-induced acid hypersecretion. However, histamine-induced acid secretion was not affected by cromolyn sodium. It is concluded that the acid hypersecretion induced by cysteamine is mediated in part by histamine release.