Background: Hypertonic saline (HTS) is an effective treatment for patients with increased intracranial pressure (ICP) secondary to traumatic brain injury (TBI). The ideal concentration for use in these patients is not well defined. The aim of our study was to compare Glasgow coma scale (GCS) and mortality of patients after administration of 3% vs. 23.4% HTS in the initial resuscitation. Methods: We performed a retrospective analysis of patients admitted to the surgical intensive care unit (ICU) under the trauma service with a diagnosis of TBI who received HTS during initial resuscitation. Patient medical records were reviewed to collect data including in-hospital mortality, ICU length of stay, hospital length of stay, GCS at the time of admission and discharge, serum sodium and serum osmolality values at 24, 48 and 72 h after arrival, acute kidney injury and severe hypernatremia. Results: Patients ≥ 18 years of age admitted to trauma ICU with a diagnosis of TBI. Pregnant, incarcerated, or non-traumatic intracranial hemorrhage patients were excluded. Thirty-one patients were included in the study. The 3% arm included 21 patients, and 23.4% arm had 10 patients. All patients received 3% HTS continuous infusion following initial bolus. Median injury severity scores (ISS) were 22 vs. 25 in the 3% vs. 23.4% HTS groups, respectively (P = 0.37). There was no difference in in-hospital mortality between the two groups (52.4% vs. 50.0%, P = 0.45). There was a significant improvement in GCS at discharge, 8.3% vs. 44.4% in 3% HTS vs. 23.4% HTS arms, respectively (P = 0.029). Patients reaching goal serum sodium and serum osmolality at 24 h was significantly higher in the 23.4% group (33.3% vs. 70.0%; P = 0.028 and 35.7% vs. 77.8%; P = 0.026, respectively). Significant increase in incidence of severe hypernatremia in the 23.4% arm was noted (0.0% vs. 40.0%, P = 0.009). Conclusion: This study demonstrates no significant difference in inhospital mortality for patients who received 3% vs. 23.4% HTS. Significantly higher percentage of patients receiving 23.4% HTS reached goal serum sodium and osmolality levels at 24 h with a concomitant significantly increased rate of severe hypernatremia.