Background: Acute carbon monoxide poisoning is a common environmental emergency worldwide. Treatment options are limited to normobaric oxygen therapy with a nonrebreather face mask or endotracheal tube and hyperbaric oxygen. The aim of this study is to determine the half-life of carboxyhemoglobin (COHb) in adult patients admitted to the emergency department with acute carbon monoxide poisoning receiving high flow nasal cannula (HFNC) oxygen. Device tolerability and patient comfort with the high flow nasal cannula were also evaluated. Methods: This study was conducted between January 2017 and February 2018 in two academic emergency departments. Venous blood samples were obtained at 10 minute intervals to determine the rate of elimination of COHb. Patient comfort was evaluated by a verbal numeric rating scale. The primary outcome was the determination of the half-life of COHb. The secondary outcome was device tolerability and patient comfort with the high flow nasal cannula oxygen delivery system. Results: A total of 33 patients were enrolled in the study. The mean baseline COHb level of the patients was 22.5% (SD 8%). The mean half-life of carboxyhemoglobin was determined as 36.8 minutes (SD 9.26 min) with high flow nasal cannula oxygen. COHb levels were halved during the first 40 minutes in 22 (67%) of the study patients. Twenty of the patients receiving HFNC oxygen did not report intolerance or discomfort. Among the 11 patients who requested a change in the flow rate, the median verbal numeric rating score was 7. After decreasing the flow rate, the median verbal numeric rating score was 9. Conclusion: High flow nasal cannula oxygen is an easy, safe, comfortable and effective method to reduce COHb. HFNC may be a promising alternative method if it is validated as effective in future studies with clinical outcomes.