Background: In this study, we explored whether early application of the prone position (PP) can improve severe hypoxemia and respiratory failure in coronavirus disease 2019 (COVID-19) patients with spontaneous breathing.Methods: This is a prospective observational study of severe, critically ill adult COVID-19 patients admitted to the intensive care unit. All vital parameters were recorded in real time for all patients. Moreover, the results of chest computed tomography (CT), when available, were analyzed.Results: PP was applied in 21 patients who were breathing spontaneously. The application of PP was associated with a significant increase in oxygen saturation measured by pulse oximetry (SpO2) from 82%±12% to 96%±3% (P<0.001) 1 hour later. Moreover, PP was associated with a significant reduction in respiratory rate from 31±10 to 21±4 breaths/min (P<0.001). Furthermore, the number of patients who exhibited signs of respiratory distress after PP was reduced from 10 (47%) to 3 (14%) (P=0.04). Early PP application also led to a clear improvement on CT imaging. It was not, however, associated with a reduction in mortality rate or in the use of invasive mechanical ventilation (P>0.05 for both).Conclusions: Our study confirmed that the early application of PP can improve hypoxemia and tachypnea in COVID-19 patients with spontaneous breathing. Randomized controlled trials are needed to confirm the beneficial effects of PP in COVID-19 patients with spontaneous breathing.