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Background: Increased intracranial pressure (ICP) occurring after traumatic brain injury (TBI) is associated with increased morbidity and mortality. If appropriate treatments are not initiated, brain herniation can occur and lead to death. Previously, the Brain Trauma Foundation recommended mannitol as the first-choice hyperosmolar agent. However, in 2016, they retracted this recommendation, citing a lack of sufficient supporting evidence. Current research shows that hypertonic saline (HTS) also decreases ICP., Objectives: To compare the efficacy of HTS and mannitol in lowering ICP in patients with TBI., Data Sources: A search was conducted up to June 1, 2019, using PubMed, Embase, CINAHL, and Web of Science. Selected articles compared mannitol and HTS in adults with TBI, with the measured outcome of reduced ICP. Four meta-analyses, three randomized controlled trials, and one retrospective cohort study met the inclusion criteria., Conclusions: Hypertonic saline is an effective alternative to mannitol for increased ICP. Three studies suggested HTS may be superior to mannitol. Conclusions were limited by sample size and methodological differences, such as varying concentrations and doses, and inclusion of patients without TBI in their studies., Implications for Practice: Evidence demonstrates HTS to be as effective as mannitol for ICP reduction. Further research in a large multicenter clinical trial is needed to compare these two agents for superiority in the management of increased ICP. Providers should consider the properties of each agent, adverse effects, and potential benefits when selecting a hyperosmotic agent., Competing Interests: Competing interests: The authors report no conflicts of interest., (Copyright © 2019 American Association of Nurse Practitioners.)