Oxygen supplementation is recommended after traumatic brain injury (TBI) but excessive oxygen may be harmful. The aim of this study was to investigate the effect of supplemental oxygen or high/low inspiratory oxygen fraction (FiO2 ) for TBI patients on in-hospital mortality. We searched Medline (Pubmed), EMBASE and the Cochrane Library for interventional and observational studies fulfilling the following criteria: TBI patients >17years (population); initial use of supplemental oxygen/high (≥0.6) FiO2 (intervention) vs no supplemental oxygen/low (<0.6) FiO2 (control) for spontaneously breathing or mechanically ventilated TBI patients, respectively with in-hospital mortality as primary outcome. Secondary outcomes were 30-day and 1-year mortality, length of stay in hospital or intensive care unit, days on mechanical ventilation, complications, and neurological impairment. We screened 4846 citations. Two interventional studies comparing high vs low FiO2 for mechanically ventilated TBI patients were included. No difference in in-hospital mortality was found. The first study found a statistically significant shorter length of stay in the intensive care unit for the high FiO2 -group (6.5 [4.6-11.4] vs. 11.4 [5.8-17.2] days, p=0.02). The second study found a lower disability at 6months in the high FiO2 -group with low disability in 25 (73.5%) vs. 15 (44.1%), moderate disability in 9 (26.5%) vs. 16 (47.1%), and severe disability in 0 (0.0%) vs. 3 (8.8%), p=0.02. Evidence on the effect of initial use of high/low FiO2 for TBI patients on in-hospital mortality was extremely limited. Evidence on the use of supplemental oxygen for spontaneously breathing TBI patients is lacking.