Substance P-like immunoreactivity (SP-li) is decreased in duodenal samples of animals treated with a single dose of an ulcerogen such as dulcerozine, mepirizole or cysteamine. Unlike dulcerozine- or mepirizole-induced ulcers the degree of cysteamine-induced duodenal lesions is inversely correlated with the levels of duodenal SP-li. A significant decrease in duodenal SP-li was observed at 24 h, but not at 6 h after a single oral dose of cysteamine. These findings show that endogenous SP may play an important local role in duodenal ulcerogenesis.