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INTRODUCTION: In fighter aircraft, long-duration high-altitude sorties are typically interrupted by refueling excursions to lower altitude. In normoxia, excursions to moderate cabin altitude may increase the occurrence of venous gas emboli (VGE) at high cabin altitude. The aim was to investigate the effect of hyperoxia on VGE and decompression sickness (DCS) during alternating high and moderate altitude exposure. METHODS: In an altitude chamber, 13 healthy men were exposed to three different conditions: A) 90 min at 24,000 ft (7315 m) breathing normoxic gas (54% O₂; H-NOR); B) 90 min at 24,000 ft breathing hyperoxic gas (90% O₂; H-HYP); and C) three 30-min exposures to 24,000 ft interspersed by two 30-min exposures to 18,000 ft (5486 m) breathing 90% O₂ (ALT-HYP). VGE occurrence was evaluated from cardiac ultrasound imaging. DCS symptoms were rated using a scale. RESULTS: DCS occurred in all conditions and altogether in 6 of the 39 exposures. The prevalence of VGE was similar in H-NOR and H-HYP throughout the exposures. During the initial 30 min at 24,000 ft, the prevalence of VGE was similar in ALT-HYP as in the other two conditions, whereas, after the first excursion to 18,000 ft, the VGE score was lower in ALT-HYP than in H-NOR and H-HYP. DISCUSSION: Hyperoxic excursions from 24,000 to 18,000 ft reduces VGE occurrence, presumably by facilitating diffusive gas exchange across the bubble surfaces, increasing the share of bubble content contributed by oxygen. Still, the excursions did not abolish the DCS risk. Ånell R, Grönkvist M, Gennser M, Eiken O. Hyperoxic effects on decompression strain during alternating high and moderate altitude exposures . Aerosp Med Hum Perform. 2021; 92(4):223230.