Predictors of outcomes are essential to identifying severe COVID-19 cases and optimizing treatment and care settings. The respiratory rate-oxygenation (ROX) index, originally introduced for predicting the failure of non-invasive support in acute hypoxemic respiratory failure (AHRF), has not been extensively studied over time during hospitalization. This multicenter prospective observational study analyzed COVID-19-related AHRF patients admitted to eight Italian hospitals during the second pandemic wave. The study assessed the ROX index using receiver operator characteristic curves and areas under the curve with 95% confidence intervals to predict treatment failure, defined as endotracheal intubation (ETI) or death. A total of 227 patients (69.2% males) were enrolled, with a median arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio at admission of 248 (interquartile range: 170-295). Nearly one-third (29.5%) required ETI or died during hospitalization. Those who experienced treatment failure were older (median age 70 versus 61 years, p<0.001), more likely to be current or former smokers (8.5% versus 6.4% and 42.4% versus 25.5%, p=0.039), had a higher prevalence of cardiovascular diseases (74.6% versus 46.3%, p<0.001), and had a lower PaO2/FiO2 ratio at presentation (median 229 versus 254, p=0.014). Gender, body mass index, and other comorbidities showed no significant differences. In patients who failed treatment, the ROX index was higher at presentation and worsened sharply by days 3 and 4. Conversely, in patients who survived without requiring ETI, the ROX index remained stable and reduced after 5-6 days. The ROX index's predictive ability improved notably by the third day of hospitalization, with the best cut-off value identified at 8.53 (sensitivity 75%, specificity 68%). Kaplan-Meier curves indicated that a ROX index of 8.53 or lower on days 1, 2, or 3 was associated with a higher risk of treatment failure. Thus, a single ROX index assessment on day 3 is more informative than its variability over time, with values of 8.53 or lower predicting non-invasive respiratory support failure in hospitalized COVID-19 patients.