Caffeine augmented formation of gastric lesions in rats exposed to restraint plus water-immersion stress for 3 h, together with inhibition of gastric secretion and gastric motility. The etiology of the lesion aggravation by caffeine was studied by measuring several parameters which were relevant to the mucosal defensive factors. Caffeine increased the susceptibility of gastric mucosa to erosive action of acid when simultaneously combined with the stress procedure. Injection of caffeine via an intraperitoneal route, but not via an intraarterial route, caused a decrease in gastric tissue blood flow when no marked fall in body temperature was seen. This indicates that the caffeine-induced decrease in gastric tissue blood flow is not due to its direct action on the gastric mucosal vessels. Hexosamine content of gastric wall tissues, however, was not significantly changed in caffeine-pretreated rats at 3 h after stress. These results suggest that caffeine aggravates stress-induced gastric lesions through some mechanism in reducing mucosal blood flow which is responsible for liability of mucosal autodigestion.