Implementing in-hospital evidence-based traumatic brain injury (TBI) guidelines improves severe TBI patient outcomes. Prehospital interventions by emergency medical services (EMS) may also mitigate secondary brain injury. The EPIC study analyzes use of prehospital Brain Trauma Foundation guidelines TBI management by Arizona EMS and clinical outcomes for moderate, severe and critical TBI patients. This is a controlled, before-after, multisystem, intention-to-treat designs study. Patient outcome in the preimplementation phase (P1) versus outcomes in the postimplementation phase (P3) were compared. 21852 patients were included (P1=15228, P3=6624). Interventions included oxygen administration to prevent/treat hypoxia, airway interventions to optimize oxygenation/ventilation, preventing hyperventilation using age appropriate ventilation rate and other parameters, and prevention/treatment of hypotension with IV isotonic fluids. Although guideline implementation did not show improvement in overall survival to discharge in TBI patients, survival improvement in the severely injured subgroup and the severe/intubated subgroup were observed. These findings support widespread adoption of the prehospital guidelines for TBI patients.