Hypertonic resuscitation fluids are known to be effective in restoring circulating volume in the hypovolemic trauma patient. Previous studies have suggested that hypertonicity might exert effects on immune cells leading to an altered host response. The present studies evaluated the effect of hypertonic resuscitation on the development of lung injury in a hemorrhagic shock model in which antecedent shock primes for increased lung neutrophil sequestration in response to intratracheal LPS. Resuscitation with hypertonic saline significantly reduced albumin leak, bronchoalveolar lavage fluid neutrophil counts, and the degree of histopathologic injury compared with resuscitation with Ringer’s lactate. Both in vivo and in vitro data suggest that this beneficial effect may be related to altered adhesion molecule expression by the neutrophil. Specifically, hypertonicity induced shedding of L-selectin and prevented LPS-stimulated expression and activation of CD11b, both of which might contribute to reduced sequestration in the lung. Impaired up-regulation of lung ICAM-1 may have also participated, although ex vivo studies suggest that alterations in neutrophils were sufficient to account for the effect. Lung cytokine-induced neutrophil chemoattractant did not differ between animals resuscitated with hypertonic saline vs Ringer’s lactate. Considered together, these studies demonstrate a possible novel approach to inhibiting organ injury in disease processes characterized by neutrophil-mediated damage.