The administration of oral S-adenosylmethionine (SAMe) (100 mg/kg body weight) was well tolerated by the rat gastroduodenal tract. Moreover, rats given SAMe exhibited a significant increase in non-protein sulfhydryl groups of gastroduodenal mucosa as compared with control animals. The abilities of SAMe and misoprostol, a prostaglandin E1 analogue, to protect the gastric mucosa against necrosis induced by various noxious stimuli (ethanol, aspirin, stress) were also compared in standardized, experimental rat models. Pretreatment with SAMe or misoprostol significantly and to the same extent reduced gastric mucosal injury. The experiments described herein indicate that SAMe, a molecule used for the treatment of osteoarthritis, can exert a gastric cytoprotective effect in animals. As preliminary data have shown that this effect may also be reproduced in humans, SAMe seems to provide a therapeutic advantage, in contrast to currently available nonsteroidal anti-inflammatory agents.