Background: Nasal high-frequency oscillatory ventilation (NHFOV) has been described as supplying the combined advantages of nasal CPAP (NCPAP) and HFOV. However, its effect on preterm infants needs to be further elucidated. Our objective was to assess whether NHFOV could reduce intubation and PCO 2 levels as compared with NCPAP during the postextubation phase in preterm infants. Methods: This was a single-center, randomized, controlled trial, and it was registered at clinicaltrials.gov (NCT03140891) and conducted between May 2017 and May 2018. Ventilated infants born at less than 37 weeks’ gestational age and ready to be extubated were included and randomized to either the NHFOV or NCPAP group. Primary outcomes were the incidence of reintubation within 1 week and the PCO 2 level within 6 h. Results: A total of 206 preterm infants were included. Of them, 127 (61.7%) were diagnosed with respiratory distress syndrome, 53 (25.7%) with ARDS, and 26 (12.6%) with both respiratory distress syndrome and ARDS. Comparing with NCPAP, NHFOV significantly reduced the reintubation rate (16:87 vs 35:68; 95% CI, 0.18-0.70; P =.002), especially in the subgroup with a gestational age of ≤ 32 weeks (12:34 vs 25:20; 95% CI, 0.12-0.68; P =.004). The PCO 2 level was also significant lower in the NHFOV group (49.6 ± 8.7 vs 56.9 ± 9.9; 95% CI, –9.95 to –4.80; P = <.001). Moreover, NHFOV significantly reduced the reintubation rate in preterm infants with ARDS (10:33 vs 21:15; 95% CI, 0.08-0.57; P =.002). Conclusions: NHFOV was shown to be superior to NCPAP in avoiding reintubation, especially in very preterm infants and those infants diagnosed with ARDS. Trial Registry: ClinicalTrials.gov; No.: NCT03140891; URL: www.clinicaltrials.gov © 2019 American College of Chest Physicians