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Background: Jet nebulizers are commonly used for bronchodilator therapy in COPD. High-flow nasal cannula with vibrating mesh nebulizer (HFNC-VMN) is a recently developed system; however, few studies have compared the efficacy of bronchodilator administration via HFNC-VMN to jet nebulizer in stable COPD. This study aimed to compare the effect of salbutamol administered via HFNC-VMN versus jet nebulizer on airway and lung function in subjects with stable COPD., Methods: This randomized non-inferiority crossover physiologic study enrolled subjects with stable COPD. Salbutamol was nebulized via HFNC-VMN or jet nebulizer in random order with a 4-h washout period between crossover sequences. Spirometry, lung volume, and impulse oscillometry were performed at baseline and after each intervention. The primary outcome was change in FEV 1 from baseline. Secondary outcomes included changes in other respiratory-related parameters and nebulization time compared between the 2 devices., Results: Seventeen subjects were enrolled. HFNC-VMN and jet nebulizer both significantly improved FEV 1 from baseline ( P = .005 and P = .002, respectively). The difference between respiratory resistance at 5 Hz and 20 Hz significantly decreased after HFNC-VMN compared to baseline ( P = .02), while no significant change was observed after jet nebulizer ( P = .056). Area of reactance and resonant frequency of reactance were both significantly decreased ( P = .035 and P = .03, respectively), and respiratory reactance at 5 Hz significantly increased ( P = .02) in the HFNC-VMN group compared to baseline indicating improved lung mechanics, with no significant changes with the jet nebulizer. HFNC-VMN had a shorter nebulization time (6 [5-9] min vs 20 [16-22] min, respectively, P < .001)., Conclusions: Bronchodilator therapy via HFNC-VMN was not inferior to jet nebulizer for subjects with stable COPD and can significantly improve airway oscillometry mechanics and decrease nebulization time compared to jet nebulizer., Competing Interests: Dr Brochard discloses relationships with Medtronic Covidien, Fisher & Paykel, Philips, Sentec, Air Liquide Medical Systems, GE Healthcare, and St. Michael's Hospital. Dr Chow discloses relationships with Thorasys Thoracic Medical Systems and AstraZeneca Canada. The remaining authors have disclosed no conflicts of interest., (Copyright © 2024 by Daedalus Enterprises.)