Previous studies have provided strong evidence to support the concepts that in the rat histamine is the chemical mediator of gastric acid secretion and that histamine plays an essential role in the pathogenesis of stress ulcers. The present experiments indicate that the role of histamine in the pathogenesis of stress ulcers in rats is probably mediated through stimulation of gastric acid secretion. In particular, we found a strong negative correlation between intragastric pH and the incidence of stress ulcers. Furthermore, intragastric administration of Basal-jel® (a nonabsorbable antacid) afforded significant protection against stress ulcers without preventing the sharp increase in histidine decarboxylase activity in response to stress.