The mucosa was removed from the distal esophagus in 35 dogs divided into three groups according to the presence or absence of gastroesophageal reflux and gastric hypersecretion. Partial or complete re-epithelization of the denuded segment by columnar mucus-secreting cells took place. Re-epithelization by squamous epithelium predominated in preparations with a competent inferior esophageal sphincter, while total or nearly total replacement by columnar cells characterized those preparations with gastroesophageal reflux and gastric hypersecretion. Peristalsis persisted in the operated portion of the esophagus as disclosed by esophageal manometry, although contractions were sometimes repetitive and prolonged. Measurement of potential difference was useful in monitoring the re-epithelization process. These experiments support the concept that the columnar-lined distal esophagus ("Barrett's esophagus") may be an acquired condition in which squamous epithelium destroyed by gastroesophageal reflux is replaced, through creeping substitution, by columnar cells of gastric or junctional origin.