Background High-flow nasal oxygen therapy (HFNOT) may be a suitable alternative for noninvasive ventilation (NIV) in chronic interstitial lung disease (ILD) during an episode of acute respiratory failure (ARF). Patients and methods Consecutive ILD patients who had ARF and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2/FiO2) of 300 mmHg or less were randomly assigned to NIV or HFNOT. The primary outcome was the need for intubation. Secondary outcomes were in-hospital mortality and ventilator-free days. Results A total of 70 patients with ILD were included. The rate of intubation was 20.6% (seven of 34 patients) in the HFNOT group and 22.2% (eight of 36) in the NIV group (P=0.87). The ventilator-free days at day 28 was higher in the HFNOT group (20±5 vs. 16±7 days in the NIV group; P=0.008). The rate of in-hospital mortality was 26.5% in the HFNOT group versus 30.6% in the NIV group (P=0.71). Conclusion HFNOT improved patient comfort and the ventilator-free days in patients with ILD and ARF, despite no difference in the rate of intubation when compared with NIV.