Subcutaneous administration of mepirizole (60 and 200 mg/kg) and cysteamine (100 and 300 mg/kg) to fasted rats consistently induced localized villous damage to the proximal duodenum after 6 to 8 hr. The severity of the damage in animals treated with the low doses remained unchanged at 12 hr. With the high doses, however, well-defined deep ulcers were evident by that time, the incidence being high. The agents caused a significant accumulation of highly acidic gastric contents for 6 to 8 hr, but the accumulated gastric contents had markedly decreased by 12 hr. The intraduodenal pH in these animals was significantly lowered for 8 hr with the low doses, but for 12 hr with the high doses. Both mepirizole and cysteamine significantly delayed gastric emptying which was quantitated by weighing the food residue in refed animals. This delay in emptying was observed for 6 to 8 hr with the low doses and for 12 hr with the high doses. We conclude that this prolonged accumulation of gastric contents for up to 8 hr, resulting in a continuous lowering of the intraduodenal pH for 12 hr, is a crucial factor for the progression from duodenal villous damage to visible ulcers in response to mepirizole and cysteamine.