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Lactated Ringer's (LR) and normal saline (NS) are both used for resuscitation of injured patients. NS has been associated with increased resuscitation volume, blood loss, acidosis, and coagulopathy compared with LR. We sought to determine if pre-hospital LR is associated with improved outcome compared with NS in patients with and without traumatic brain injury (TBI). We included patients receiving pre-hospital LR or NS from the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study. Patients with TBI (Abbreviated Injury Scale [AIS] head ≥3) and without TBI (AIS head ≤2) were compared. Cox proportional hazards models including Injury Severity Score (ISS), AIS head, AIS extremity, age, fluids, intubation status, and hospital site were generated for prediction of mortality. Linear regression models were generated for prediction of red blood cell (RBC) and crystalloid requirement, and admission biochemical/ physiological parameters. Seven hundred ninety-one patients received either LR (n = 117) or NS (n = 674). Median ISS, AIS head, AIS extremity, and pre-hospital fluid volume were higher in TBI and non-TBI patients receiving LR compared with NS ( p < 0.01). In patients with TBI (n = 308), LR was associated with higher adjusted mortality compared with NS (hazard rate [HR] = 1.78, confidence interval [CI] 1.04-3.04, p = 0.035). In patients without TBI (n = 483), no difference in mortality was demonstrated (HR = 1.49, CI 0.757-2.95, p = 0.247). Fluid type had no effect on admission biochemical or physiological parameters, 6-hour RBC, or crystalloid requirement in either group. LR was associated with increased mortality compared with NS in patients with TBI. These results underscore the need for a prospective randomized trial comparing pre-hospital LR with NS in patients with TBI. [ABSTRACT FROM AUTHOR]