High-flow oxygen through nasal cannula (HFNC) provides adequate oxygenation and can be an alternative to noninvasive ventilation (NIV) for patients with hypoxemic respiratory failure. The aim of the present study was to assess the efficacy of HFNC versus NIV in hypercapnic respiratory failure. Patients (n = 40) who were admitted to the Emergency Department of Alexandra Hospital due to hypercapnic respiratory failure (PaCO2 ≥ 45 mmHg) were randomized assigned into two groups, i.e., an intervention group (use of HFNC, n = 20) and a control group (use of NIV, n = 20). During their hospitalization in the Intensive Care Unit, vital signs (respiratory and heart rate, arterial blood pressure) and arterial blood gases (ABG) were closely monitored on admission, after 24 h and at discharge. No difference between the two groups regarding the duration of hospitalization and the use of HFNC or NIV was observed (p > 0.05). On admission, the two groups did not differ in terms of gender, age, body mass index, APACHE score, predicted death rate, heart rate, arterial blood pressure and arterial blood gases (p > 0.05). Respiratory rate in the HFNC group was lower than in the NIV group (p = 0.023). At discharge, partial carbon dioxide arterial pressure (PaCO2) in the HFNC group was lower than in the NIV group (50.8 ± 9.4 mmHg versus 59.6 ± 13.9 mmHg, p = 0.024). The lowerPaCO2 in the HFNC group than in the NIV group indicated that HFNC was superior to NIV in the management of hypercapnic respiratory failure.