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Objective: To compare the efficacy of high-flow nasal cannula oxygen therapy (HFNC) and non-rebreather face mask (NRFM) in the treatment of mild acute carbon monoxide poisoning (ACOP) in reducing carboxyhemoglobin (COHb) , and to explore the feasibility of HFNC in the treatment of ACOP. Methods: Patients with mild ACOP with COHb >10% who were admitted to the emergency department of Northern Jiangsu People's Hospital from January 2015 to December 2020 were analyzed, and those with altered consciousness, mechanical ventilation and those requiring hyperbaric oxygen therapy were excluded. The patients were divided into HFNC group and NRFM group according to the oxygen therapy used in the emergency department. The COHb decline value and COHb half-life in the two groups were observed. Results: Seventy-one patients were enrolled, including 39 in the NRFM group and 32 in the HFNC group. The baseline COHb in the HFNC group was 24.8%±8.3%, and that in the NRFM group was 22.5%±7.1%, with no significant difference between the two groups ( t =1.27, P =0.094) . At 60 min, 90 min and 120 min of treatment, COHb in both groups decreased, but the COHb in HFNC group was lower than that in NRFM group at the same time point ( P <0.05) . After 1 h of treatment, the COHb decrease in the HFNC group (16.9%±4.5%) was significantly higher than that in the NRFM group (10.1%±7.8%) ( t =4.32, P =0.013) . The mean half-life of COHb in the HFNC group (39.3 min) was significantly lower than that in the NRFM group (61.4 min) ( t =4.69, P =0.034) . Conclusion: HFNC treatment of mild ACOP can rapidly reduce blood COHb level, it is a potential oxygen therapy method for clinical treatment of ACOP.