PurposeWe investigated the efficacy and safety of a high-flow nasal cannula (HFNC) at different flow rates compared to noninvasive ventilation (NIV) in patients with acute chronic obstructive pulmonary disease (COPD) exacerbations. MethodsThis prospective, randomized, single-blind study assigned patients to one of three study groups. The NIV group (n = 47) received bilevel positive airway pressure. The HFNC-30 (n = 44) and HFNC-50 (n = 46) groups received HFNC therapy at flow rates of 30 and 50 L/min, respectively. Demographic and clinical characteristics and arterial blood gas parameters before and 30, 60, and 120 min after treatment were compared among the treatment groups. ResultsThis study included 137 consecutive patients with acute exacerbations of COPD, comprising 90 males and 47 females, with a mean age of 68.1 ± 10.5 years. A total of 21 patients (15.33 %) were intubated, and the overall mortality rate was 10.2 %. The mean PaCO2 levels on admission were 64.69 ± 10.81, 61.51 ± 9.03, and 62.29 ± 9.87 in the NIV, HFNC-30, and HFNC-50 groups, respectively, with no significant differences observed (p = 0.372). A significant reduction in mean PaCO2 was observed in all treatment groups at 30, 60, and 120 min (p < 0.05 for all). However, the ΔPaCO2 at 60 min was significantly higher in the HFNC-30 group compared to the NIV group (p = 0.042). Additionally, neither intubation rates nor 28-day mortality differed among the treatment groups (p = 0.368 and p = 0.775, respectively). ConclusionHFNC was not inferior to NIV in improving arterial blood gas parameters, particularly PaCO2 in patients with COPD exacerbations, especially those with hypercarbia. Moreover, HFNC at a flow rate of 30 L/min was superior to NIV for reducing PaCO2 levels at 60 min. Trial RegistryNational Library of Medicine Clinical Trial Registry; No.: NCT06495086; URL: https://clinicaltrials.gov/study/NCT06495086