Background <p>Awake prone positioning (APP) was readily experimented with patients intubated for acute hypoxemic respiratory failure (AHRF) during COVID-19 pandemic, and it effectively improved several patients’ outcomes. Yet, its effects in non-intubated patients with AHRF are uncertain. This study explored the potential of APP to reduce endotracheal intubation and help weaning from non-invasive ventilatory support in AHRF, in comparison to standard care alone.</p> Methods <p>Thirty-one non-intubated patients with AHRF were randomly assigned to receive either standard care alone or APP along with standard care. APP was delivered in intermittent sessions throughout the day, the duration of which was determined by the patient’s tolerance. Daily APP sessions were dropped if F_iO2 improved by 40% from baseline or endotracheal intubation became necessary.</p> Results <p>APP was tolerable by patients for a median of 3.5&#xa0;h per day, without serious adverse events in most patients. Endotracheal intubation, mortality, and weaning success in patients who received APP were comparable to those in the control group. There were no significant differences in time to endotracheal intubation, time to weaning, or duration of ICU stay. Improvement in oxygenation was comparable in both groups, but reduction in both heart rate and respiratory rates were significantly more notable in APP group.</p> Conclusion <p>Using APP along ventilatory support in management of AHRF results in comparable improvement of oxygenation and weaning success as using ventilatory support alone. Endotracheal intubation and mortality are not altered by provision of APP, though marginally improving both outcomes.</p>