OBJECTIVES: This study aimed to assess the feasibility and safety of use of high-flow oxygen (HFO) through the endotracheal tube for apnea testing during brain death evaluation. DESIGN: Prospective, interventional, single-center study. SETTING: ICUs at the Orléans University Hospital, France. PATIENTS: All adult patients meeting the criteria for clinical brain death and requiring an apnea test were eligible. INTERVENTIONS: Fifteen patients underwent two successive apnea tests in the same order, each lasting 10 minutes: The first apnea test used 8 L/min of oxygen via a T-piece without a positive end-expiratory pressure valve connected to the endotracheal tube (standard test). The second apnea test used HFO at 50 L/min and Fio2 of 1.0 through a specialized device connected to the endotracheal tube. Arterial blood gases were measured every 2 minutes during both apnea tests. The primary objective was to investigate the feasibility and safety of use of HFO through the endotracheal tube for apnea testing compared with use of a T-piece in patients whose clinical examination was consistent with brain death and required an apnea test. MEASUREMENTS AND MAIN RESULTS: All patients reached Paco2 greater than 60 mm Hg by the end of both apnea tests. At 10 minutes, Paco2 was 69.1 ± 5.9 mm Hg with the T-piece and 71.3 ± 6.0 mm Hg with HFO. Pao2 decreased significantly during the T-piece apnea test (from 404 ± 115 to 215 ± 118 mm Hg) but remained stable with HFO apnea test (from 342 ± 114 to 308 ± 92 mm Hg). CONCLUSIONS: HFO through the endotracheal tube is feasible and safe method for apnea testing. In patients with confirmed brain death via the standard apnea test, HFO yielded consistent diagnostic results while maintaining better oxygenation. Further research, particularly randomized trials, is needed to confirm the benefits of HFO in apnea testing.