We conducted this prospective self-crossover controlled trial to compare the efficacy and safety of 10 % hypertonic saline (HS) and 20 % mannitol in doses of similar osmotic burden for the treatment of increased intracranial pressure (ICP) in patients with large hemispheric infarction (LHI). Patients with LHI were enrolled from January 2017 to January 2018. We used an alternating treatment protocol to compare the effects of HS with mannitol given for episodes of increased ICP in patients with LHI. Indicators such as ICP, mean arterial pressure (MAP) and cerebral perfusion pressure (CPP) were continuously monitored at regular intervals for 240 min after initiation of infusion. Electrolytes, plasma osmolality and renal functions were measured before and 240 min after initiation of infusion to compare the efficacy and safety of the two drugs. A total of 49 episodes of increased ICP occurred in 14 patients with LHI, of which 24 were infused with 10 % HS and 25 with 20 % mannitol. Both the treatments were equally effective in reducing ICP (P < 0.01). The differences in the duration and degree of reduction were not significant between the groups (P > 0.05). Although both the osmolar agents decreased MAP, the degree was greater in the mannitol group (P < 0.05) at T120. The increase in CPP was greater in the HS group compared with the mannitol group (P < 0.05) at T120. However, HS was associated with faster heart rate (HR) and higher serum chloride levels (P < 0.05). Changes in serum sodium levels and osmolality were not significant between the groups in spite of being higher in the HS group. Both the drugs can serve as first-line agents for treating intracranial hypertension caused by LHI and should be selected rationally according to the differences in efficacy and adverse effects. Copyright © 2020 Elsevier B.V. All rights reserved.