A single s.c. administration of histamine dose-dependently (5-20 mg/kg) induced villous damage of the proximal duodenum in 24-hr fasting rats. Time course studies indicate that histamine (20 mg/kg) induced severe exfoliation of the epithelial cells at the villous tips of the duodenal mucosa 0.5 hr after administration. The damage, however, tended to heal with time, and recovery was nearly complete 8 hr later. This villous damage was significantly inhibited by pretreatment with sodium bicarbonate given orally or cimetidine, omeprazole and NC-1300 given subcutaneously. Histamine (20 mg/kg) significantly stimulated gastric acid secretion and lowered the intraduodenal pH for 1 hr. Gastric content was significantly greater than that in the control group for 1 hr after histamine administration, probably due to stimulated gastric secretion and delayed emptying. We conclude that a single administration of histamine induces microscopical duodenal damage by stimulation of gastric acid secretion, but the damage heals with time, probably as a result of the short periods of acid stimulation and delayed emptying.