Context: Hypertonic saline (HTS) is a pharmacologic therapy used in patients with severe traumatic brain injuries to decrease intracranial pressure (ICP) associated with cerebral edema. Aims: The purpose of this study was to compare ICP reduction between fixed doses of 23.4% HTS and weight-based doses. Setting and Design: This was a retrospective study that included adult patients at a level 1 trauma center who had nonpenetrating traumatic brain injury, an ICP monitor, and received at least one dose of 23.4% HTS. Subjects and Methods: Doses were classified as either high weight-based (>0.6 ml/kg), low weight-based (<0.6 ml/kg), or standard fixed dose (30 ml). Only doses given within 5 days post-injury were evaluated. Percent reduction in ICP was compared pre- and post-dose between dosing groups, and each dose was evaluated as a separate episode. Statistical Analysis: The primary and secondary endpoints for the study were analyzed using mixed-model, repeated-measures analysis of covariance. Results: A total of 97 doses of HTS were evaluated. The primary endpoint of ICP reduction showed a 42.5% decrease in ICP after the administration of a high weight-based dose, a 36.7% reduction after a low weight-based dose, and a 31.5% reduction after a fixed dose. There was no significant relationship between dose group and percent change in ICP (P = 0.25). A sub-analysis of doses received within 48 h postinjury found a significant relationship between both dose group and percent change in ICP, and initial ICP and percent change in ICP (P = 0.04, and <0.0001 respectively). Conclusions: Our data did not show a significant difference between fixed- and weight-based doses of 23.4% HTS for ICP reduction.