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The morphology of esophageal mucosal damage induced by trypsin was investigated in an experimental model, where the rabbit esophagus was perfused in situ with a control solution (physiologic NaCl) and trypsin (1 mg/ml). The results indicate that trypsin has an adverse effect on esophageal mucosa. In light microscopy infiltration of leucocytes in the submucosa and later ulcerative changes in the mucosa were seen. Scanning electron microscopy showed detachment of superficial cells and later deeper lesions, displaying denuted intramucosal collagen bundles with erythrocytes. In transmission electron microscopy significant widening of the intercellular spaces could be seen. This suggests that in clinical situations trypsin refluxed from duodenum into stomach and further to esophagus has an adverse effect on esophageal mucosa and may have importance in the pathogenesis of clinical reflux esophagitis. Because of the relatively high pH-optimum trypsin may have importance only under nonacidic or alkaline conditions.