Aim: In patients who do not have any indication for hyperbaric oxygen (O2) treatment, the main treatment to eliminate carbon monoxide (CO) is by giving O2 using a face mask. In the absence of a non-rebreathing face mask, a diffuser mask (DMG) or simple face mask (SMG) is an option that can be used for treatment. There are insufficient data about the acute efficacy of these masks. To study the ability of DMG and SMG in lowering carboxyhemoglobin (COHb) levels after the first hour of O2 treatment in patients with CO intoxication.Materials and Methods: This was a prospective randomized clinical study conducted in patients aged ≥16 years old who were diagnosed with CO intoxi-cation. They were randomly given 15 L/min O2 (from hospital central O2 supplies) treatment with DMG (n=29) or SMG (n=52). Partial pressure of O2 (PaO2), carbon dioxide, and COHb levels and saturation of O2 were measured before and after 1 h of treatment.Results: A total of 81 (42 female and 39 male) patients with a mean age of 39.1±14.7 years were included in the study. There were no differences with regard to age, gender, body mass index, comorbidity, source of CO, initial symptoms, and initial COHb levels before treatment. After the first hour of treatment, DMG had lower mean COHb (mg/dL) levels (9.6±5.0 vs. 12.8±6.2, p=0.0203) and higher mean PaO2 levels (224.4±56.5 vs. 183.4±63.7, p=0.0046) than SMG.Conclusion: Diffuser mask (DMG) appears to be better than simple face mask (SMG) in the first hour of treatment of CO intoxication.