Although hypertonic saline (HTS) decreases intracranial pressure (ICP) with traumatic brain injury (TBI), its effects on survival and post-discharge neurologic function are less certain. We assessed the impact of HTS administration on TBI outcomes and hypothesized that favorable outcomes would be associated with larger amounts of 3% saline. This is a retrospective study of consecutive-patients with the following criteria: blunt trauma, age 18-70 years, intracranial hemorrhage, Glasgow Coma Scale score (GCS) 3-12, and mechanical ventilation ≥ 5 days. The need for craniotomy or craniectomy denoted surgical decompression patients. Amounts of HTS were during the first-5 trauma center days. Traits for the 112 patients during 2012-2016 were as follows: GCS, 6.8 ± 3.2; subdural hematoma, 71.4%; cerebral contusion, 31.3%, ICP device, 47.3%; surgical decompression, 51.8%; ventilator days, 14.8 ± 6.7; trauma center mortality, 13.4%; and no commands at 3 months 35.5%. In surgically decompressed patients, trauma center mortality was greater with ≤ 8.0 mEq/kg sodium (38.9%) than with > 8.0 mEq/kg (7.5%; P = 0.0037). In surgically decompressed patients, following commands at 3 months was greater with ≥ 1400 mEq sodium (76.9%) than with < 1400 mEq (50.0%; P = 0.0489). For trauma center surviving non-decompression patients with no ICP device, those following commands at 3 months received more sodium (513 ± 784 mEq) than individuals not following commands (82 ± 144 mEq; P = 0.0142). For patients with a GCS 5-8, following commands at 3 months was greater with ≥ 1350 mEq sodium (92.3%) than with < 1350 mEq (60.0%; P = 0.0214). In patients with subdural hematoma or cerebral contusion, following commands at 3 months was greater with ≥ 1400 mEq sodium (84.2%) than with < 1400 mEq (61.8%; P = 0.0333). Patients with ICP > 20 mmHg for ≤ 10 hours (mean hours 2.0) received more sodium (16.5 ± 11.5 mEq/kg) when compared to ICP elevation for ≥ 11 hours (mean hours 34) (9.4 ± 6.3 mEq/kg; P = 0.0139). These observations demonstrate that hypertonic saline administration in patients with complex traumatic brain injury is associated with 1) mitigation of intracranial hypertension, 2) trauma center survival, and 3) following commands at 3 months post-injury.