Cerebral injury is seen in one of three patients with multiple traumas; thus efficient shock treatment is a most important measure against the development of secondary brain damage. Small-volume resuscitation in severe hemorrhagic shock by hypertonic/hyperoncotic saline/dextran has been shown to instantaneously normalize cardiac output and to raise systemic blood pressure. In this study, the fluid regimen was compared with hypertonic mannitol to investigate their therapeutic efficacy in intracranial hypertension. The experiments were performed in rabbits subjected to a focal lesion of the brain to induce acute, vasogenic brain edema. The resulting intracranial hypertension was enhanced in a standard manner by inflation of an epidural balloon until an intracranial pressure (ICP) of 17 mm Hg was obtained. Intravenous administration of either 7.2% saline/10% dextran-60 or of 20% mannitol rapidly decreased the elevated ICP. After the first injection, ICP lowering was maintained longer by the mannitol than by the hypertonic saline/dextran, whereas no differences in duration of ICP lowering were found when the infusions of these solutions were repeated. The systemic blood pressure increased after injection of the saline/dextran solution, but it tended to decrease after injection of the mannitol. Transient increases in plasma osmolality, colloid-osmotic pressure, and plasma-Na+ were more pronounced after administration of the saline/dextran solution than after the administration of the mannitol. No difference in the tissue water content between the traumatized and contralateral hemisphere was observed in the animals receiving mannitol; however, after saline/dextran infusion, the water content was somewhat increased in the exposed hemisphere but decreased in the nonexposed, contralateral hemisphere (decreased to a point even below the corresponding level of animals who received the mannitol). The increase of the cerebral water content of the traumatized hemisphere was associated with a respective increase of the cerebral Na+ content and a (nonsignificant) decrease of the K+ content. The present findings demonstrate that the hypertonic/hyperoncotic saline/dextran was as efficient as the mannitol in reducing ICP that had been increased by a cerebral lesion and a space-occupying mass; the underlying mechanisms responsible for the reduction might differ. Because of the powerful hemodynamic properties of the saline/dextran in circulatory shock, administration of the solution in patients with multiple traumas and head injury might be particularly advantageous for the prevention of secondary ischemic brain damage.