question: INTRODUCTION A significant proportion of patients with COVID-19 present with a rapidly progressing severe acute respiratory failure (ARF). OBJECTIVES We aimed to assess the therapeutic success of high-flow nasal oxygen (HFNO) in severe ARF in the course of COVID-19 in a noncritical care setting as well as to identify predictors of HFNO failure. PATIENTS AND METHODS This prospective observational study was conducted between March and December 2020. We enrolled all consecutive hospitalized patients with confirmed SARS-CoV-2 infection in whom HFNO therapy was used. The primary outcome measure was death or endotracheal intubation within 30 days from admission. RESULTS Of the 380 patients with COVID-19, 116 individuals (30.5%) requiring HFNO due to severe pneumonia were analyzed. The primary outcome, defined as death or endotracheal intubation within 30 days from admission, occurred in 54 patients (46.6%). The overall 30-day mortality was 30.2% (35/116) in the entire cohort and 64.7% (34/51) among patients requiring endotracheal intubation. A multivariable analysis revealed that the ROX index measured within the first 12 hours of therapy below 3.85 was related to increased mortality (hazard ratio, 5.86; 95% CI, 3.03-11.35) compared with the ROX index of 4.88 or higher. CONCLUSIONS This study suggests that nearly half of patients treated with HFNO due to severe COVID-19 pneumonia will require mechanical ventilation. The ROX index is a useful tool for predicting HFNO failure in this population.