Abstract Background Extubation failure is associated with increased morbidity and mortality, but cannot be safely predicted or avoided. High-flow nasal cannula (HFNC) prevents postextubation respiratory failure in low-risk patients. Objective To demonstrate that HFNC reduces postextubation respiratory failure in high-risk non-hypercapnic patients compared with conventional oxygen. Methods Randomized, controlled multicenter trial in patients who passed a spontaneous breathing trial. We enrolled patients meeting criteria for high-risk of failure to randomly receive HFNC or conventional oxygen for 24 h after extubation. Primary outcome was respiratory failure within 72-h postextubation. Secondary outcomes were reintubation, intensive care unit (ICU) and hospital lengths of stay, and mortality. Statistical analysis included multiple logistic regression models. Results The study was stopped due to low recruitment after 155 patients were enrolled (78 received high-flow and 77 received conventional oxygen). Groups were similar at enrollment, and all patients tolerated 24-h HFNC. Postextubation respiratory failure developed in 16 (20%) HFNC patients and in 21 (27%) conventional patients [OR 0.69 (0.31–1.54), p = 0.2]. Reintubation was needed in 9 (11%) HFNC patients and in 12 (16%) conventional patients [OR 0.71 (0.25–1.95), p = 0.5]. No difference was found in ICU or hospital length of stay, or mortality. Logistic regression models suggested HFNC [OR 0.43 (0.18–0.99), p = 0.04] and cancer [OR 2.87 (1.04–7.91), p = 0.04] may be independently associated with postextubation respiratory failure. Conclusion Our study is inconclusive as to a potential benefit of HFNC over conventional oxygen to prevent occurrence of respiratory failure in non-hypercapnic patients at high risk for extubation failure. Registered at Clinicaltrials.gov NCT01820507.