Background: Supplemental oxygen (SO) is one of the most commonly administered drugs in trauma patients and is recommended by guidelines. However, evidence supporting uniform administration is sparse, and excess oxygen use has been shown to be harmful in other patient populations. We hypothesized that SO may be harmful in patients with oxygen saturation > 97%. Methods: Patients with available information on SO-therapy in the American Trauma Quality Improvement Program 2017 database were included. Patients were categorized into 3 groups according to Emergency Department (ED) oxygen saturation: (1) saturation < 94%; (2) saturation 94%-97%; (3) saturation 98%-100%. Primary outcome was in-hospital mortality with comparisons made between patients who received SO or not. Secondary outcome was acute respiratory distress syndrome (ARDS). Patients were compared after propensity score matching. Results: Overall, 864 340 patients were identified. Mean age was 47.4 ± 24.4 years, and median injury severity score was 9. SO was associated with an increased risk of in-hospital mortality: (all patients: adjusted odds ratio [aOR] with 95% confidence interval [CI] 3.07 [2.92-3.22], ED saturation <94%: 2.63 [2.38-2.91], ED saturation 94%-97%: 2.71 [2.47-2.97], ED saturation >97%: 3.38 [3.16-3.61]. Same pattern was seen for in-hospital ARDS: (aOR 1.79, 95% CI [1.59-2.02], ED saturation <94%: aOR 1.75, 95% CI [1.37-2.24], ED saturation 94%-97%: aOR 1.81, 95% CI [1.43-2.29, ED saturation >97%: aOR 2.31, 95% CI [1.92-2.79]). Conclusion: Based on propensity matched, registry data for trauma patients, the administration of SO was associated with a higher incidence of in-hospital mortality and ARDS. The highest risk was found in patients with an ED saturation >97%.