The pathway which results in a loss of intestinal barrier function and transepithelial transfer of macromolecules after cutaneous thermal injury is unknown. To determine the enhanced absorption pathway, transepithelial transport of horseradish peroxidase (HRP) was examined ultrastructurally after a thermal injury. Within 6 h after the injury, increased HRP uptake was seen in the portal and systemic blood with the maximal increase in uptake measured at 18 h postinjury; permeability returned to normal by 72 h postinjury. Morphologically, the increased uptake was found to be transcellular through ultrastructurally normal intestinal absorptive cells. Occasional focal regions of enhanced HRP uptake were found and this enhanced uptake was attributed to focal intestinal epithelial disruptions. This increase in intestinal permeability represents a transient loss of intestinal barrier function and potentially allows absorption of macromolecules such as endotoxin from the intestinal lumen into the portal circulation early after thermal injury.