Esophagitis is now recognized to occur in the absence of gastric acid. We have compared the potentially injurious effect of physiologic concentrations of trypsin, taurodeoxycholate, and pepsin at pH 7.5 using a continuously perfused rabbit esophagus model. Gross and microscopic esophagitis, tissue hemorrhage, and indexes of esophageal mucosal barrier function were assessed. Trypsin caused the most severe morphologic changes and hemorrhage, but only minimal disruption of the esophageal mucosal barrier. In contrast, taurodeoxycholate caused only minimal esophagitis and no hemorrhage, but caused extensive disruption of the esophageal mucosal barrier. Neither pepsin, at this alkaline pH, nor alkaline test solution alone (pH 7.5) caused esophageal injury by any criteria. These results show that the degree of esophageal mucosal barrier disruption cannot always be equated with the degree of morphologic injury, and that different components of the gastroduodenal contents may differ in their sites or mechanisms of esophageal injury. Finally, among the gastroduodenal contents we tested, trypsin was the most noxious agent in alkaline reflux esophagitis in terms of causing mucosal erosion, inflammation, and hemorrhage.