Background: The role of high-flow nasal cannula (HFNC) and CPAP in COVID-19 are controversial. The objective of the study was to evaluate the impact of the application of a non-invasive respiratory support (NIRS) algorithm on clinical outcomes in COVID-19 subjects with acute respiratory failure (ARF).Methods: We performed a single center prospective observational study of subjects with respiratory failure from COVID-19 managed with high-flow nasal cannula (HFNC) and CPAP+HFNC (combined therapy). The main outcome was the intubation rate, which defined failure of therapy. We also analyzed the role of the ROX index ([SpO2/FiO2]/respiratory rate) to predict the need for intubation.Results: From June to December 2020, 113 subjects with COVID-19 respiratory failure were admitted to our respiratory intermediate care unit (RICU). HFNC was applied in 65 subjects (57.52%) and combined therapy in 48 (42.47%). A total of 83 subjects (73.45%) were successfully treated with NIRS. The intubation rate was 26.54 %, and overall mortality was 14.15%. Mortality rate in intubated subjects was 55.2%. ROX index of 6.28 at 12 hours predicted NIRS failure, with 97.6% of sensitivity and 51.8% of specificity.Conclusions: Data from our cohort managed on RICU showed that combined NIRS are feasible with favorable outcomes. Further prospective studies are required.