Object The authors sought to describe changes in clinical management associated with brain tissue oxygen (PbO₂) monitoring and how these changes affected outcomes and resource utilization. Methods The cohort study comprised 629 patients admitted to a Level I trauma center with a diagnosis of severe traumatic brain injury over a period of 3 years. Hospital mortality rate, neurological outcome, and resource utilization of 123 patients who underwent both PbO₂ and intracranial pressure (ICP) monitoring were compared with the same measures in 506 patients who underwent ICP monitoring only. The main outcomes were hospital mortality rate, functional independence at hospital discharge, duration of mechanical ventilation, hospital length of stay, and hospital cost. Multivariable regression with robust variance was used to estimate the adjusted differences in the main outcome measures between patient groups. The models were adjusted for patient age, severity of injury, and pathological features seen on head CT scan at admission. Results On average, patients who underwent ICP/PbO₂ monitoring were younger and had more severe injuries than patients who received ICP monitoring alone. Relatively more patients treated with PbO₂ monitoring received osmotic therapy, vasopressors, and prolonged sedation. After adjustment for baseline characteristics, the hospital mortality rate was, if anything, slightly higher in patients undergoing PbO₂-guided management than in patients monitored with ICP only (adjusted mortality difference 4.4%, 95% CI −3.9 to 13%). Patients who underwent PbO₂-guided management also had lower adjusted functional independence scores at hospital discharge (adjusted score difference −0.75, 95% CI −1.41 to −0.09). There was a 27% relative increase (95% CI 6–53%) in the median hospital length of stay when the PbO₂ group was compared with the ICP-only group. Conclusions The mortality rate in patients with traumatic brain injury whose clinical management was guided by PbO₂ monitoring was not reduced in comparison with that in patients who received ICP monitoring alone. Brain tissue oxygen monitoring was associated with worse neurological outcome and increased hospital resource utilization.