Injury to the intestinal mucosa is a life-threatening problem in a variety of clinical disorders, including hemorrhagic shock, trauma, burn, pancreatitis and heat stroke. However, the susceptibility to injury of different regions of intestine in these disorders is not well understood. We compared histological injury across the small intestine in two in vivo mouse models of injury, hemorrhagic shock (30% loss of blood volume) and heat stroke (peak core temperature,42.4°C). In both, areas near the duodenum showed significantly greater mucosal injury and reductions in villi height. To determine if these effects were dependent on circulating factors, additional experiments were performed on isolated intestinal segments to test for permeability to 4 kDa FITC-dextran. The segments were exposed to hyperthermia (42°C for 90 min) moderate simulated ischemia (PO230; PCO2 60 Torr; pH = 7.1), severe ischemia: (PO₂20; PCO₂80 Torr; pH6.9), or severe hypoxia (PO₂0, PCO₂35 Torr) for 90 min, and each group was compared to sham controls. All treatments resulted in marked elevations in permeability within segments near the duodenum. In severe hypoxia or hyperthermia, permeability was also moderately elevated in the jejunum and ileum, but in moderate or severe ischemia, permeability was unaffected in these regions. The results demonstrate increased susceptibility of proximal regions of the small intestine to acute stress-induced damage, irrespective of circulating factors. The predominant injury in the duodenum may impact the pattern of acute inflammatory responses arising from breach of the intestinal barrier and may be useful knowledge for designing therapeutic strategies.