Summary Discrete duodenal ulcers were produced in a small percentage of rats by continuous infusion of two gastric secretogogues, pentagastrin + carbachol. When nicotine sulfate was added to the mixture, nearly all rats developed duodenal ulcers, and the latter were up to five times more severe and up to four times more numerous, depending on the dose of nicotine. Nicotine alone was not ulcerogenic. It is suggested that nicotine sensitizes to ulcer formation by reducing secretion of pancreatic juice (by inhibiting the action of secretin). The lack of pancreatic juice, which is alkaline, prevents neutralization of acid flowing from the stomach, and thus permits acid to attack the duodenal mucosa. Nicotine may be responsible for the higher incidence of peptic ulcer among smokers.