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OBJECTIVES: Since there are difficulties in establishing effective treatments for COVID-19, a vital way to reduce mortality is an early intervention to prevent disease progression. This study aimed to evaluate the performance of patients with COVID-19 with acute hypoxic respiratory failure according to pulmonary impairment in the awake-prone position, outside of the intensive care unit (ICU). METHODS: A prospective observational cohort study was conducted on COVID-19 patients under noninvasive respiratory support. Clinical and laboratory data were obtained for each patient before the treatment and after they were placed in the awake-prone position. To identify responders and non-responders after the first prone maneuver, receiver operating characteristic curves with sensitivity and specificity of the PaO2/FiO2 and SpO2/FiO2 indices were analyzed. The maneuver was considered positive if the patient did not require endotracheal intubation for ventilatory assistance. RESULTS: Forty-eight patients were included, and 64.6% were categorized as responders. The SpO2/FiO2 index was effective for predicting endotracheal intubation in COVID-19 patients regardless of lung parenchymal damage (area under the curve 0.84, cutoff point 165, sensitivity 85%, specificity 75%). Responders had better outcomes with lower hospital mortality (hazard ratio [HR]=0.107, 95% confidence interval [CI]: 0.012-0.93) and a shorter length of stay (median difference 6 days, HR=0.30, 95% CI: 0.13-0.66) after adjusting for age, body mass index, sex, and comorbidities. CONCLUSIONS: The awake-prone position for COVID-19 patients outside the ICU can improve oxygenation and clinical outcomes regardless of the extent of pulmonary impairment. Furthermore, the SpO2/FiO2 index discriminates responders from non-responders to the prone maneuver predicting endotracheal intubation with a cutoff under or below 165.