Hyperosmotic agents have been used in the past 40 years for managing patients with severe traumatic brain injury (TBI) to lower intracranial pressure (ICP). Mannitol was the main agent used in the past, but hypertonic saline (HTS) is gaining popularity. There are few studies comparing the efficacy of mannitol versus HTS in terms of ICP reduction, and there is no data to evaluate the effect of either agent on cerebral perfusion pressure (CPP). This study is a case control study using prospectively collected data from the TBI-trac database to evaluate the effect of mannitol and HTS on both high ICP and low CPP. 25 patients were identified in the HTS group that have an exact match in the mannitol group in the 1:1 match cohort, while there were 24 patients identified in the HTS group with exact match in the mannitol group in the 1:2 match cohorts. In both cohorts, the total number of days and the cumulative burden of high ICP/low CPP were significantly lower in the HTS group. There is also evidence that the HTS group has a lower burden of low CPP. There was no significant difference in systemic hypotension or vasopressor use. In summary, this case control study shows HTS to be more effective than mannitol in terms of lowering the burden of ICP and maintaining CPP.