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Abstract BACKGROUND: Members of the public will soon be taking commercial suborbital spaceflights with significant G x (chest-to-back) acceleration potentially reaching up to 6 G x . Pulmonary physiology is gravity-dependent and is likely to be affected, which may have clinical implications for medically susceptible individuals. METHODS: During 2-min centrifuge exposures ranging up to 6 G x , 11 healthy subjects were studied using advanced respiratory techniques. These sustained exposures were intended to allow characterization of the underlying pulmonary response and did not replicate actual suborbital G profiles. Regional distribution of ventilation in the lungs was determined using electrical impedance tomography. Neural respiratory drive (from diaphragm electromyography) and work of breathing (from transdiaphragmatic pressures) were obtained via nasoesophageal catheters. Arterial blood gases were measured in a subset of subjects. Measurements were conducted while breathing air and breathing 15 oxygen to simulate anticipated cabin pressurization conditions. RESULTS: Acceleration caused hypoxemia that worsened with increasing magnitude and duration of G x . Minimum arterial oxygen saturation at 6 G x was 86 1 breathing air and 79 1 breathing 15 oxygen. With increasing G x the alveolar-arterial (A-a) oxygen gradient widened progressively and the relative distribution of ventilation reversed from posterior to anterior lung regions with substantial gas-trapping anteriorly. Severe breathlessness accompanied large progressive increases in work of breathing and neural respiratory drive. DISCUSSION: Sustained high-G acceleration at magnitudes relevant to suborbital flight profoundly affects respiratory physiology. These effects may become clinically important in the most medically susceptible passengers, in whom the potential role of centrifuge-based preflight evaluation requires further investigation. Pollock RD, Jolley CJ, Abid N, Couper JH, Estrada-Petrocelli L, Hodkinson PD, Leonhardt S, Mago-Elliott S, Menden T, Rafferty G, Richmond G, Robbins PA, Ritchie GAD, Segal MJ, Stevenson AT, Tank HD, Smith TG. Pulmonary effects of sustained periods of high-G acceleration relevant to suborbital spaceflight . Aerosp Med Hum Perform. 2021; 92(7):633641.