The intestinal epithelium normally provides a barrier function that prevents absorption of potentially harmful materials from the intestinal lumen. It has been postulated but never demonstrated that a cutaneous thermal injury will result in increased small-intestinal permeability. In a standardized 20% body surface area full-thickness scald injury, with polyethylene glycol 3350 and horseradish peroxidase used as permeability probes, small-intestinal permeability was examined regionally in an everted intestinal sac model. In the normal animals, the upper (proximal) and lower (distal) small intestine were less permeable to these probes than the middle segment. Within 6 hours after the injury, an increase in the mucosal uptake and transmural permeability was seen in all three small-intestinal segments; the most dramatic increase in permeability occurred in the ileum, p less than 0.01. The maximum increase in permeability was seen at 18 hours, and permeability was normal by 72 hours after the injury. This increase in intestinal permeability may represent a transient failure of the intestinal barrier function and may allow absorption of potentially toxic macromolecules from the intestinal lumen into the portal circulation early after thermal injury. Absorption of these macromolecules, such as endotoxin, may be potentially harmful by direct toxic actions or potentially helpful by activation of the immune system.