Airway acid aspiration leads to severe microvascular lung injury and pulmonary edema. Recent studies have demonstrated that other conditions associated with microvascular injury such as sepsis and burns can be effectively treated with low-volume hypertonic saline (HTS). Thus, the present study aimed to test whether HTS attenuates aspiration-induced lung injury in the rat. Intratracheal administration of 0.2 ml of 0.1NHCl (n= 7) induced pulmonary leukosequestration [myeloperoxidase (MPO) activity +446 ± 34%,P< 0.05; bronchoalveolar lavage (BAL) fluid neutrophil count +178 ± 23%,P< 0.05], edema (+43 ± 6%,P< 0.01), and microvascular permeability defect (BAL protein concentration +675 ± 34%,P< 0.01). These changes were associated with tissue hypoxia (skeletal muscle PO₂, 49 ± 8 mm Hg,P< 0.05) and elevated serum TNFα (750 ± 38 pg/ml,P< 0.01). HTS (2400 mosmole/liter) at 5 ml/kg, administered 20 min after aspiration (n= 7), reduced lung pulmonary edema by 58 ± 7% (P< 0.05) and improved tissue oxygen tension (PO₂, 85 ± 7 mm Hg,P< 0.05) but failed to alter lung MPO and BAL fluid protein and leukocyte count response. Also, HTS did not reduce TNFα response to aspiration. These data point to a potential therapeutic role for low-volume HTS in treating aspiration-induced lung injury. In addition, our data suggest that HTS is acting by rapidly shifting fluid from the pulmonary interstitium to the intravascular compartment because it did not inhibit the inflammatory response to aspiration.