Since 1991, there has been an alarming increase in the number of unexplained physiological events (UPEs) reported and experienced by pilots of jet fighters across different fleets. The UPEs have resulted in grounding some airframes, loss of aircraft, and even loss of life. There is no single agreed-upon root cause of UPEs that has been identified, and therefore there is no reliable corrective action. This author analyzed the literature related to other industries where artificial hyperoxic gas mixes are employed and where similar adverse reports have been reported. I hypothesize that UPEs are caused by high-dose oxygen delivery in excess of officially approved oxygen schedules while airflow rates are often inadequate, at a time when the positive pressure breathing feature of their oxygen regulator is not used. In a setting where pulmonary vital capacity is adversely affected by G-maneuvers and oxygen- and G-induced atelectasis, tidal volume is reduced by flight gear, and effective gas exchange is not supported by adequate ventilation, these factors combine to produce respiratory acidosis, followed by acute respiratory distress syndrome, CO2 narcosis, and coma. Reports from field data related to incidents in F-18S/H, showing that emergency oxygen did not correct the hypoxia-like symptoms including long-lasting periods of incapacitation and prolonged headaches, lend support to our hypothesis.