The morphology of esophagitis, both in the presence and absence of acid, was studied by light microscopy and transmission and scanning electron microscopy. For this purpose the rabbit esophagus was isolated in situ and perfused with agents known to cause esophageal mucosal damage (HCl, pepsin, taurocholate, and deoxycholate). In addition, changes in the permeability of the plasma membrane of the esophageal epithelial cells were assessed by staining the esophageal epithelium with trypan blue and antinuclear antibodies. The results indicate that HCl alone causes relatively few changes in the esophageal epithelium. However, when combined with pepsin or taurocholate, severe ulcerative changes were caused within an hour. Deoxycholate, which is formed in the upper gastrointestinal tract under nonacidic conditions, also causes severe damage. Further, it was shown that the esophagitis caused by pepsin and bile salts are clearly morphologically different. Bile salts affect primarily the cell membrane and intracellular organelles, while pepsin seems to affect the intercellular substance causing the epithelial cells to be shed. In contrast, the presence or absence of acid per se does not seem to influence the nature of the epithelial damage, since the lesions caused by the two bile salts (deoxycholate vs taurocholate + HCl) were morphologically similar.