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Background: High-flow nasal cannula therapy has been shown to be useful in the treatment of patients with acute respiratory failure caused by severe acute respiratory syndrome-coronavirus disease-2. The ROX index can help predict the success of high-flow nasal cannula in coronavirus disease-19-related acute respiratory failure. However, the timing of ROX- index assessment is still unclear to protect the patients from complications due to early or delayed intubation. Aims: To evaluate the relation between ROX index patterns within the first 48 hours of the therapy and high-flow nasal cannula success rates. The secondary aim was to determine other possible predictors of high-flow nasal cannula failure. Study design: A cross-sectional study. Methods: Patients admitted to the intensive care unit between April 2020 and January 2022 with coronavirus disease-19-related acute respiratory failure and treated with high-flow nasal cannula were included in the study. Patients' demographics, clinical characteristics and laboratory findings at intensive care unit admission; ROX indices at initiation, 2nd, 8th, 12th, 24th and 48th hours of high-flow nasal cannula; and outcomes were recorded. Results: In the study period, 69th patients were managed with high- flow nasal cannula for at least 2 hours. While 24 patients (34.7%) were successfully weaned from high-flow nasal cannula, 45 (65.3%) patients failed. Overall mortality at day 28 was 44.9%. ROX indices were lower in the high-flow nasal cannula failure group through the 12th, 24th, and 48th hours of the therapy, no significant change was observed (P = 0.33). While an overall increase in ROX index patterns were detected in patients weaned from high-flow nasal cannula (P = 0.002). Pairwise analyses revealed that ROX indexes remain stable during the first 8th hours in both groups, then improved to 12th hours of the therapy in successfully high-flow nasal cannula-weaned patients. Conclusion: Dynamic assessments of the ROX indexes could be more suggestive rather than a point assessment to identify patients who would benefit from the high-flow nasal cannula or deteriorate in coronavirus disease-19 related acute respiratory failure. [ABSTRACT FROM AUTHOR]