Acute liver failure (ALF) is a rare condition characterized by the development of encephalopathy in the absence of chronic liver disease. Cerebral edema occurs in up to 80% of patients with Grade IV encephalopathy. In the current prospective randomized controlled clinical trial, we examined the effect of induced hypernatremia on the incidence of intracranial hypertension (IH) in patients with ALF. Thirty patients with ALF and Grade III or IV encephalopathy were randomized. Patients in Group 1 (n = 15) received the normal standard of care. Patients in Group 2 (n = 15) received standard care and hypertonic saline (30%) via infusion to maintain serum sodium levels of 145-155 mmol/L. Intracranial pressure (ICP) was monitored in all patients with a subdural catheter (Camino Systems, San Diego, CA) for up to 72 hours after inclusion. Serum sodium levels became significantly different from the levels observed in the control group at 6 hours (P <.01). Over the first 24 hours, norepinephrine dose increased relative to baseline in the control group (P <.001; 13 patients) but not in the treatment group. ICP decreased significantly relative to baseline over the first 24 hours in the treatment group (P =.003; 13 patients) but not in the control group. The incidence of IH, defined as a sustained increase in ICP to a level of 25 mm Hg or greater, was significantly higher in the control group (P =.04). In conclusion, induction and maintenance of hypernatremia can reduce the incidence and severity of IH in patients presenting with ALF.