Background: Severe traumatic brain injury (TBI) is associated with a high mortality rate and those that survive commonly have permanent disability. While there is a broad consensus that appropriate prehospital treatment is crucial for a favorable neurological outcome, evidence to support currently applied treatment strategies is scarce. In particular, the relationship between prehospital treatments and patient outcomes is unclear. The BRAIN-PROTECT study therefore aims to identify prehospital treatment strategies associated with beneficial or detrimental outcomes. Here, we present the study protocol. Study Protocol: BRAIN-PROTECT is the acronym for BRAin INjury: Prehospital Registry of Outcome, Treatments and Epidemiology of Cerebral Trauma. It is a prospective observational study on the prehospital treatment of patients with suspected severe TBI in the Netherlands. Prehospital epidemiology, interventions, medication strategies, and nonmedical factors that may affect outcome are studied. Multivariable regression based modeling will be used to identify confounder-adjusted relationships between these factors and patient outcomes, including mortality at 30 days (primary outcome) or mortality and functional neurological outcome at 1 year (secondary outcomes). Patients in whom severe TBI is suspected during prehospital treatment (Glasgow Coma Scale score ≤ 8 in combination with a trauma mechanism or clinical findings suggestive of head injury) are identified by all four helicopter emergency medical services (HEMS) in the Netherlands. Patients are prospectively followed up in 9 participating trauma centers for up to one year. The manuscript reports in detail the objectives, setting, study design, patient inclusion, and data collection process. Ethical and juridical aspects, statistical considerations, as well as limitations of the study design are discussed. Discussion: Current prehospital treatment of patients with suspected severe TBI is based on marginal evidence, and optimal treatment is basically unknown. The BRAIN-PROTECT study provides an opportunity to evaluate and compare different treatment strategies with respect to patient outcomes. To our knowledge, this study project is the first large-scale prospective prehospital registry of patients with severe TBI that also collects long-term follow-up data and may provide the best available evidence at this time to give useful insights on how prehospital care can be improved.