Background: High-flow nasal cannula (HFNC) oxygen is becoming an integral part of respiratory failure management. Effects of HFNC on arterial blood gas (ABG) parameters especially partial carbon dioxide (PaCO2) require further investigation to provide insight into the efficacy and safety of the treatment. Methods: Acute respiratory failure patients with sequential ABG parameters before and after initiating HFNC between June 2015 and June 2017 were analyzed in a tertiary academic center. Patients' baseline characteristics were evaluated and sequential ABG changes were compared and subgrouped as chronic obstructive pulmonary disease (COPD), respiratory acidosis, hypercapnia, and high lactate. Results: A total of 120 patients were enrolled in the study. There was a significant difference between the mean partial pressure of oxygen in arterial blood (PaO2), lactate, and peripheral oxygen saturation (SpO2) values between sequential ABGs after HFNC (P <0.001). In the COPD group (n=32), there was a significant difference between initial ABG means of PaO2, lactate, and SpO2 values and sequential ABG means (p<0.001). Hypercapnic patients PaCO2 levels were significantly lower after HFNC (p<0.001), while in the COPD group there was no significant change in PaCO2 values (p=0.068). Conclusions: Treatment with HFNC produced improvement of blood gas parameters in subjects with acute respiratory failure in the emergency department (ED). These results suggest that HFNC can be used in hypercapnic patients as well as hypoxemic patients. Further randomized controlled studies required to establish the impact of HFNC in the ED.