Hypertonic saline (HTS) resuscitation improves outcome after trauma. We studied the effect of HTS on immune function. In vitro T-cell proliferation of human and rabbit peripheral blood mononuclear cells (PBMC) was doubled at 25 mM increased extracellular Na+ concentrations. Further increased hypertonicity (more than 40 mM with human cells, and 80 mM with rabbit cells) caused progressive suppression of proliferation. Human and rabbit monocyte functions (tumor necrosis factor production) were augmented by 300% at 30 mM hypertonicity, indicating that HTS-enhanced accessory cell function of monocytes may cause increased T-cell proliferation. Substitution of HTS with KCl also enhanced T-cell proliferation, suggesting an involvement of osmotic effects. HTS (up to 30 mM) increased Ca2+i of nonstimulated human PBMC. HTS injection in rabbits increased cell-mediated immune function (delayed-type hypersensitivity reaction). Our findings suggest that increased plasma osmolality may up-regulate cellular immune function. HTS resuscitation of trauma patients may thus reverse posttraumatic immunosuppression and reduce the risk of sepsis.