This study examined the regional heterogeneity and site-specific changes in histology and glycoconjugate content following the induction of esophagitis and after recovery in an established animal model. Esophageal samples were excised from five sites in anesthetized opossums 24 hr after 3 consecutive days of 45-min perfusion with saline or 100 mM HCl or 1 week after acid in recovery animals. Controls exhibited significant regional differences in epithelial thickness, gland volume, glycoconjugate composition, and mast cell numbers. Acid perfusion induced erosive esophagitis and significant epithelial denudation throughout the distal 7 cm, combined with significant site-specific increases in gland lumen volume, decreases in mast cell numbers, and changes in glycoconjugate content. No differences from controls were noted in recovery animals, except for a significant increase in epithelial thickness and change in glycoconjugate content in the distal 2 cm. The results of this study highlight the impact of acid exposure on these structural defenses, but further investigation is required to explore the importance of these acid-induced changes in the pathogenesis of reflux esophagitis.