Rapid epithelial restitution is now considered one of the primary defense mechanisms of the stomach and duodenum. Because there is currently no evidence as to whether restitution occurs in human tissue, this study examined human and rabbit colonic mucosa after superficial injury and monitored the potential difference, alkaline flux, and speed and mechanisms of mucosal restitution as observed with light and electron microscopy. Luminal exposure of the in vivo rabbit colon to 100 mM HCl for 5 min or the in vitro human colon to 10 mM HCl for 10 min caused superficial mucosal injury to 76% of the epithelial surface in the rabbit and 95% in the human. The necrotic epithelial cells detached in sheets from the intact basal lamina and formed a protective mucoid layer. Morphologic evidence of restitution occurred within 15 min after injury in the rabbit and 30 min in the human, as viable nongoblet cells projected lamellipodia and migrated over the denuded basal lamina at a speed of approximately 2 microns/min. One hour after damage 61% of the mucosal surface was still damaged in the rabbit, and 86% of the human mucosal surface was damaged after 2 h. In the following 60 min restitution progressed rapidly, so that only 10% of the surface remained unrepaired in the rabbit after 2 h and 19% in the human after 3 h. Small areas with deeper injury did not repair until 5 h after damage. The potential difference dropped after mucosal injury and did not recover despite morphologic repair. Rapid epithelial restitution is considered to be a basic defense mechanism of the gastrointestinal mucosa that is obviously not necessarily related to the presence of an acidic environment in the stomach or duodenum.