Many intensive care unit patients who undergo endotracheal extubation experience extubation failure and require reintubation. Because of the high mortality rate associated with reintubation, postextubation respiratory management is crucial, especially for high-risk populations. We conducted the present study to compare the effectiveness of oxygen therapy administered using high-flow nasal cannulae (HFNC) and noninvasive positive pressure ventilation (NIPPV) in preventing reintubation among patients receiving prolonged mechanical ventilation (PMV). This single-center, prospective, unblinded randomized controlled trial was at the respiratory care center (RCC). Participants were randomized to an HFNC group or an NIPPV group (20 patients in each) and received noninvasive respiratory support (NRS) administered using their assigned method. The primary outcome was reintubation within7 days after extubation. None of the patients in the NIPPV group required reintubation, whereas 5 (25%) of the patients in the HFNC group required reintubation (P = 0.047). The 90-day mortality rates of the NIPPV and HFNC groups (four patients [20%] vs. two patients [10%], respectively) did not differ significantly. No significant differences in length of RCC stay, length of hospital stay, time to liberation from NRS, and ventilator-free days at 28-day were identified. The time to event outcome analysis also revealed that the risk of reintubation in the HFNC group was higher than that in the NIPPV group (P = 0.018). Although HFNC is becoming increasingly common as a form of postextubation NRS, HFNC may not be as effective as NIPPV in preventing reintubation among patients who have been receiving PMV for at least 2 weeks. Additional studies evaluating HFNC as an alternative to NIPPV for patients receiving PMV are warranted.ClinicalTrial.gov ID: NCT04564859; IRB number: 20160901R.Trial registration: ClinicalTrial.gov (https://clinicaltrials.gov/ct2/show/NCT04564859).