The BOOST-2 trial indicated that optimising brain oxygen (PbtO2) could be a viable therapeutic target for severe traumatic brain injury (sTBI). Previous studies have suggested the safety of airway pressure release ventilation (APRV) in sTBI patients, but its effect on PbtO2 has not been demonstrated. This study is aimed to show that APRV can improve PbtO2 in sTBI patients. In a retrospective case series, two sTBI patients with controlled intracranial pressures developed refractory hypoxemia and brain hypoxia, unresponsive to traditional therapies. Treated with APRV, both patients showed improved hypoxemia and increased PbtO2 levels above 20 mm Hg without adverse effects on intracranial pressure. They recovered from hypoxemia, transitioned to assist-controlled ventilation and were discharged to rehabilitation. These cases suggest that APRV can safely and effectively improve PbtO2 in sTBI patients when other treatments fail, warranting further exploration pending results from the ongoing BOOST-3 trial.