Clinically both mannitol and hypertonic saline (HTS) have been used successfully to treat elevated intracranial pressure (ICP), although which therapy is superior is yet unclear. Most experimental data have been derived from animal models of brain injury using general anesthesia, which may not be applicable under other conditions. Our laboratory compared the efficacy of single, equi-osmolar bolus doses of HTS and mannitol in reducing elevated ICP in a lightly sedated, unrestrained rodent model of acute brain injury. Sprague-Dawley rats were mask anesthetized for craniectomy and placement of invasive monitors. Following emergence from anesthesia, continuous sedation was provided (0.25% halothane in oxygen). A focal, liquid nitrogen cold lesion was introduced to the right parietal cortex. Animals were continuously monitored and then treated with a single bolus of 0.9% saline (control group) or 11.0 mOsm/kg equivalents of either mannitol or HTS (experimental groups) at time of maximal ICP increase (60 minutes). Both mannitol and HTS reduced ICP, but HTS was more effective-53.9% reduction versus 35.0% (P < .01). The therapeutic action of HTS was also more durable, lasting up to 500 minutes whereas the mannitol treated animals were observed to return to, and overshoot the baseline elevated ICP by 10% to 25% by 120 minutes following dosing (P < .01). Despite these differences, brain water content was similar between groups. We conclude that HTS was more effective in reducing elevated ICP in this awake model of traumatic brain injury.