Hypercapnic acidosis protects against direct lung injury in in vivo and ex vivo models, however, lung injury/acute respiratory distress syndrome commonly occurs after a nonpulmonary etiology. We investigated whether therapeutic hypercapnia (TH)-deliberate elevation of carbon dioxide (CO2) tension-would protect against lung injury after splanchnic ischemia-reperfusion injury in an in vivo model. TH was associated with preservation of lung mechanics, attenuation of protein leakage, and improved oxygenation compared with control conditions. Lung protection was therapeutic as well as prophylactic. Protection was dose-dependent, but inspired CO2 concentrations above 5.0% were associated with little additional lung protection. Before lung injury, increasing FICO2 resulted in a dose-dependent increase in PaO2. Lung protection with hypercapnia occurred despite pulmonary artery pressures that were greater than observed with normocapnia. Reperfusion increased lipid peroxidation (tissue 8-isoprostane concentration) in the bowel, liver, and lung, and caused histologically apparent bowel injury; however, none of these effects was altered by TH. Therefore, TH-induced by adding CO2 to inspired gas-provides consistent protection against lung injury in terms of lung permeability, oxygenation, and lung mechanics after mesenteric ischemia-reperfusion. These data further support the emerging evidence for ongoing physiologic study of TH at the bedside.