Hypertonic saline (7.5% NaCl = HS) was compared with 20% mannitol (MAN), for the treatment of increased intracranial pressure (ICP), in a large animal model of head injury. Sheep were instrumented for hemodynamic and ICP monitoring and fluid administration. Elevated ICP (20–25 mm Hg) was produced by inflating an epidural balloon for 1 hour. Animals were then given a bolus of 250 mL of either HS (n = 7) or MAN (n = 7) and monitored for 2 hours. No significant differences in hemodynamic variables were noted between groups. The ICP decreased to the same degree in both groups during the 2 hours of observation (HS = 11 ± 3.8 mm Hg; MAN = 8 ± 2 mm Hg). Brain water contents were also similar (HS = 3.68 ± 0.09 mL H2O/g dry wt; MAN = 3.83 ± 0.08 mL H2O/g dry wt). The 7.5% NaCl was equally effective in treating elevated ICP caused by a space-occupying lesion when compared with 20% mannitol. Hypertonic saline has the additional benefit of rapid cardiovascular resuscitation of associated hemorrhagic shock with small-volume infusion.