Preliminary evidence suggests that PbtO₂ values of ≤ 15 mm Hg may be suggestive of brain tissue hypoxia. Accordingly, many neurotrauma intensive care units attempt to maintain the PbtO₂ ≥ 20 mm Hg based on the belief that this intervention will increase availability of oxygen in the brain for metabolism, and will avoid periods of brain tissue hypoxia with a 5 mm Hg buffer range. In clinical practice, one approach to managing a low PbtO₂ (< 20 torr) is to increase the delivered fraction of inspired oxygen (FiO₂). It remains unclear whether this therapy has risks as it also has the potential to increase oxidative stress. To determine if short periods of normobaric hyperoxia (2h) affect oxidative stress markers and antioxidant defenses, cerebrospinal fluid (CSF) was assessed in adults [n=11, (9 male, 2 female), mean age 26±1.8 yrs], with severe TBI (Glasgow Coma Scale score 6±1.4) before, during, and after a FiO₂=1.0 challenge. Markers of oxidative stress including lipid peroxidation (F₂-isoprostane [ELISA]) and protein oxidation (protein sulfhydryls [fluorescence]) and markers of antioxidant defenses including total antioxidant reserve (AOR) [chemiluminescence] and glutathione [fluorescence] were evaluated in CSF. Physiological parameters, [intracranial pressure (ICP), mean arterial pressure (MAP), cerebral perfusion pressure (CPP), PbtO ₂, arterial oxygen content (pO₂)] were assessed at the same time points, using a 30 minute average prior to each FiO₂ change. Mean (±SD) PbtO₂ and PaO₂ levels significantly changed for each time point, [before 27.3±7.4, 173.1±51.4; during 93.9±58.1, 385.5±108.3; and after 29.3±13.0, 171.8±45.1] a FiO₂ challenge, (p=.04; .01), respectively. Oxidative stress markers, antioxidant reserve defenses and physiological parameters did not significantly change for any time period. These preliminary findings suggest that brief periods of normobaric hyperoxia improve oxygen levels without producing local oxidative stress in brain tissue. Additional studies are required to examine extended periods of normobaric hyperoxia and application of treatment during periods of critical PbtO₂ levels.