Decompression sickness (DCS) occurs in diving, altitude chamber exposures, and unpressurized or depressurized high-altitude flights. Because DCS takes many forms, in-flight cases may be misinterpreted as hypoxia, hyperventilation, or viral illness, with resulting failure to respond appropriately. In this case, a 28-yr-old male pilot of a single-seat, tactical aircraft experienced 12 rapid pressure fluctuations while flying at 43,000 ft above sea level. He had no symptoms and decided to complete the flight, which required an additional 2 h in the air. Approximately 1 h later he began to experience fatigue, lightheadedness, and confusion, which he interpreted as onset of a viral illness. However, symptoms progressed to visual, cognitive, motor, and sensory degradations and it was with some difficulty that he landed safely at his destination. Neurologic DCS was suspected on initial evaluation by flight line medical personnel because of the delayed onset and symptom progression. He was transferred to a local Emergency Department and noted to have altered mental status, asymmetric motor deficits, and non-dermatomal paresthesias of the upper and lower extremities. Approximately 3.5 h after the incident and 2.5 h after the onset of symptoms he began hyperbaric oxygen therapy. He received partial relief at 30 min of the Navy DiveTable 6 and full resolution at 90 min; there were no recurrent symptoms at a 1-yr follow-up. This case highlights the importance of early recognition of in-flight DCS symptoms and landing as soon as possible rather than as soon as practical in all likely scenarios.