Esophagitis has been associated with the reflux of acidic gastroduodenal contents. These contents may contain not only HCl but also pepsin, bile, and pancreatic enzymes. This experiment was designed to compare the roles of these components in experimental acid esophagitis. The esophagus of the rabbit was cannulated and perfused continuously via a recirculating system with pH 2 acid test solution. Net flux of H+, K+, glucose, and hemoglobin plus the recovery of tritiated water were determined before and after the addition of pepsin, taurodeoxycholate, or trypsin. Afterward the esophageal segments were graded for gross and microscopic esophagitis. These studies show that pepsin caused significant gross and microscopic esophagitis. Moreover, pepsin also caused significant increases in H+, K+, glucose, and hemoglobin flux as well as decreased recovery of tritiated water. Taurodeoxycholate increased esophageal mucosal permeability to H+, K+, and glucose and decreased the recovery of tritiated water but did not cause significant pathologic change. Trypsin and acid alone did not result in significant esophagitis by either pathologic or ionic permeability criteria. These results show tha disruption of the esophageal mucosal barrier cannot be equated with pathologic injury and that different components of the gastroduodenal contents may have different sites or mechanisms of injury.