Traumatic brain injury (TBI) remains a major cause of death and disability, with an estimated cost of $45 billion/year in the United States alone. Patients with severe TBI, defined as those who are unconscious or only minimally responsive to external stimulation, have an especially poor prognosis. Approximately 35% of patients with severe TBI die within 6 months of injury and among those who survive, approximately 80% have life-long disabilities, representing a large unmet medical need. One of the critical barriers to progress in discovering new treatments for severe TBI is the lack of blood tests that can guide the personalization of TBI treatments so that the right treatment is administered to the right type of TBI patient. Additionally, there are no blood tests for monitoring ongoing brain injury and individual patient response to treatment. The recently funded BOOST-3 (Brain Oxygen Optimization in Severe TBI Phase 3) trial offers a unique opportunity to study and validate new blood tests for TBI. BOOST-3 will enroll 1094 participants with severe TBI from 2019 – 2023, across 47 clinical sites in the US, and represents a $32.5 M federal investment. BOOST-3 will examine whether severe TBI treatment based on values obtained brain tissue oxygen and intracranial pressure values obtained from probes inserted into the brain will improve neurologic outcome at 6 months after injury compared to treatment based on intracranial pressure monitoring only. Capitalizing on the infrastructure and the rich study population for BOOST-3, we propose conducting an ancillary biomarker study, Bio-BOOST. The main goal of Bio-BOOST is to determine how the lack of oxygen to brain tissues affects the levels of blood tests for brain injury.