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.