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Abstract Background The effects of awake prone position on the breathing pattern of hypoxemic patients need to be better understood. We conducted a crossover trial to assess the physiological effects of awake prone position in patients with acute hypoxemic respiratory failure. Methods Fifteen patients with acute hypoxemic respiratory failure and PaO2/FiO2 0.99) and ΔP L (9 [7–11] cmH2O vs. 8 [5–9], p = 0.17). Airway resistance and time constant were higher in prone vs. supine position (9 cmH2O s arbitrary units−3 [4–11] vs. 6 [4–9], p = 0.05; 0.53 s [0.32–61] vs. 0.40 [0.37–0.44], p = 0.03). Prone position increased EELI (3887 arbitrary units [3414–8547] vs. 1456 [959–2420], p = 0.002) and promoted V T distribution towards dorsal lung regions without affecting V T size and lung compliance: this generated lower dynamic strain (0.21 [0.16–0.24] vs. 0.38 [0.30–0.49], p = 0.004). The magnitude of pendelluft phenomenon was not different between study phases (55% [7–57] of V T in prone vs. 31% [14–55] in supine position, p > 0.99). Conclusions Prone position improves oxygenation, increases EELI and promotes V T distribution towards dependent lung regions without affecting V T size, ΔP L, lung compliance and pendelluft magnitude. Prone position reduces respiratory rate and increases ΔP ES because of positional increases in airway resistance and prolonged expiratory time. Because high ΔP ES is the main mechanistic determinant of self-inflicted lung injury, caution may be needed in using awake prone position in patients exhibiting intense ΔP ES. Clinical trail registeration: The study was registered on clinicaltrials.gov (NCT03095300) on March 29, 2017.