Cimetidine, an H2-receptor, antagonist, and carbenoxolone sodium, a drug used to stimulate gastric mucus synthesis and increase the life span of gastric epithelial cells, were studied to determine their possible prophylactic effect on the formation of stress ulcers, gastric transmucosal potential difference and gastric pH in rats, using a restraint stress model. The number of ulcers substantially decreased in the rat groups receiving either cimetidine or carbenoxolone pretreatment for two or more days before stress. When the drugs were used in combination, there was an additive effect, since there was a significant decrease in ulcer formation even after half a day of pretreatment. When antacids were used, there was also decreased ulcer formation with half a day of pretreatment. Gastric pH was significantly increased from control levels in all the groups treated with antacid, cimetidine and carbenoxolone. Both cimetidine and carbenoxolone, either alone or in combination, prevented the decrease in potential difference that was produced in the untreated stressed rats. This study suggests that either cimetidine or carbenoxolone, and particularly their combination, may be a useful prophylactic regimen for the prevention of stress ulceration in patients subjected to severe stress.