Mepirizole (200 mg/kg) and cysteamine (100 mg/kg) induced epithelial cell damage in the proximal duodenum of rats within 30 min after s.c. administration. The injury induced was severe 60 min later. Gastric acid secretion determined in intact animals was stimulated by these agents 30 and 60 min later when the intraluminal pH of the duodenum was significantly decreased. Duodenal blood flow was significantly decreased beginning 5 min after administration up to 60 min. Oral treatment with sodium bicarbonate (300 mg/kg), cimetidine (100 mg/kg), omeprazole or NC-1300 (gastric proton pump inhibitors, 30 mg/kg) and 16, 16-dimethyl prostaglandin E₂ (10μg/kg) protected the epithelium from damage induced by the two duodenal ulcerogens. Epithelial cell damage in the duodenum in response to mepirizole and cysteamine appears to be related to the increased gastric acid secretion followed by lowered intraduodenal pH of the duodenum having decreased blood flow.