The effect of hemorrhagic shock on gut permeability to macromolecules was investigated using fluorescein isothiocyanate dextrans (4,300 or 73,100 daltons). These were given orally, then measured in systemic blood during hemorrhage (mean arterial pressure of 30 mmHg) and reperfusion; sham-shocked animals served as controls. Hemorrhage lasting 2 h resulted in a 5-fold increase in concentration of both tracers relative to that found in control groups. Reperfusion reduced these differences, with values approximately threefold greater than those of controls after 2 h. On a molar basis, the smaller molecule was more permeant than the larger one. This study provides evidence that hemorrhagic shock physically perturbs the normal barrier function of the mucosa, permitting very large substances in the gut lumen access to the circulation. It may further explain, at least in part, previous observations that hypovolemic shock results in bacterial translocation and endotoxemia.