<b><i>Background:</i></b> Raised intracranial pressure (ICP) due to cerebral edema (CE) is central to development of hepatic encephalopathy in acute liver failure (ALF). Mannitol (MT) and hypertonic saline (HS) have been shown to improve CE. We compared the efficacy and safety of the 2 modalities. <b><i>Methods:</i></b> ALF with CE was prospectively randomized in an open study to receive either 5 mL/kg of either 3% HS, as continuous infusion; titrated every 6 hourly to achieve serum sodium of &#x3c;160 (Group A; <i>n</i> = 26) or 1 g/kg of 20% MN as a IV bolus, repeated every 6 hourly (Group B; <i>n</i> = 25) in addition to standard ALF care. Primary end-point was reduction of ICP defined as optic nerve sheath diameter &#x3c;5 mm and middle cerebral arterial pulsatility index &#x3c;1.2 at 12 h. <b><i>Results:</i></b> Fifty-one patients with ALF, hepatitis E being commonest (33.3%), median jaundice to HE interval of 8 (1–16) days, were randomized to HS (<i>n</i> = 26) or MN (<i>n</i> = 25). Baseline characteristics were comparable including King’s college criteria (&#x3e;2: 38.4% vs.40%). Overall, 61.5% patients in the HS and 56% in the MN group showed reduction in ICP at 12 h (<i>p</i> = 0.25). Rebound increase in ICP indices was noted in 5 (20%) patients in MT and none in HS (<i>p</i> &#x3c; 0.05) group. New onset acute kidney injury was common in the MT group than in the HS group. The ICU stay and 28-day transplant-free survival were not different between the groups. <b><i>Conclusions:</i></b> While both agents had comparable efficacy in reducing ICP and mortality in ALF patients was comparable, HS was significantly better in preventing reducing rebound CE with lower renal dysfunction.