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High-flow nasal cannula (HFNC) improves the clinical outcomes of nonintubated patients with acute hypoxemic respiratory failure (AHRF).To assess the effects of HFNC on gas exchange, inspiratory effort, minute ventilation, end-expiratory lung volume, dynamic compliance, and ventilation homogeneity in patients with AHRF.This was a prospective randomized crossover study in nonintubated patients with AHRF with PaO2/setFiO2 less than or equal to 300 mm Hg admitted to the intensive care unit. We randomly applied HFNC set at 40 L/min compared with a standard nonocclusive facial mask at the same clinically set FiO2 (20 min/step).Toward the end of each phase, we measured arterial blood gases, inspiratory effort, and work of breathing by esophageal pressure swings (ΔPes) and pressure time product, and we estimated changes in lung volumes and ventilation homogeneity by electrical impedance tomography. We enrolled 15 patients aged 60 ± 14 years old with PaO2/setFiO2 130 ± 35 mm Hg. Seven (47%) had bilateral lung infiltrates. Compared with the facial mask, HFNC significantly improved oxygenation (P < 0.001) and lowered respiratory rate (P < 0.01), ΔPes (P < 0.01), and pressure time product (P < 0.001). During HFNC, minute ventilation was reduced (P < 0.001) at constant arterial CO2 tension and pH (P = 0.27 and P = 0.23, respectively); end-expiratory lung volume increased (P < 0.001), and tidal volume did not change (P = 0.44); the ratio of tidal volume to ΔPes (an estimate of dynamic lung compliance) increased (P < 0.05); finally, ventilation distribution was more homogeneous (P < 0.01).In patients with AHRF, HFNC exerts multiple physiologic effects including less inspiratory effort and improved lung volume and compliance. These benefits might underlie the clinical efficacy of HFNC.