Abstract Background Standard high-flow nasal cannula (HFNC) is a respiratory support device widely used to manage post-extubation hypoxemic acute respiratory failure (hARF) due to greater comfort, oxygenation, alveolar recruitment, humidification, and reduction of dead space, as compared to conventional oxygen therapy. On the contrary, the effects of the new asymmetrical HFNC interface (Optiflow® Duet system (Fisher & Paykel, Healthcare, Auckland, New Zealand) is still under discussion. Our aim is investigating whether the use of asymmetrical HFNC interface presents any relevant difference, compared with the standard configuration, on lung aeration (as assessed by end-expiratory lung impedance (EELI) measured by electrical impedance tomography (EIT)), diaphragm ultrasound thickening fraction (TFdi) and excursion (DE), ventilatory efficiency (estimated by corrected minute ventilation (MV)), gas exchange, dyspnea, and comfort. Methods Pilot physiological crossover randomized controlled study enrolling 20 adults admitted to the Intensive Care unit, invasively ventilated for at least 24 h, and developing post-extubation hARF, i.e., PaO2/set FiO2