BACKGROUND: This study was conducted to compare the effectiveness of noninvasive ventilation (NIV) with pressure support (NIV-PSV) to noninvasive neurally-adjusted ventilatory assist (NIV-NAVA) during COPD exacerbation. METHODS: In this study, 40 subjects with COPD and acute hypercapnic respiratory failure were randomized to receive either NIV-NAVA (n ‫؍‬ 20) or NIV-PSV (n ‫؍‬ 20) via a critical care ventilator. Subjects' vital parameters, arterial blood gas values, patient-ventilator asynchrony events, and asynchrony index were noted at specific time intervals in both groups. The duration of NIV, rate of NIV failure, and length hospital stay were also recorded for these 2 modes of NIV. RESULTS: NIV-NAVA significantly reduced the total number (median [interquartile range]) of asynchrony events compared to NIV-PSV: 22 (15-32.5) versus 65 (50.75-104.25), respectively, P ‫؍‬ .002. Severe asynchrony defined as asynchrony index > 10% was also significantly lower in NIV-NAVA than in NIV-PSV (P < .001). There was no significant difference between the 2 groups regarding improvement in gas exchange and vital parameters. Rate of failure of NIV (P ‫؍‬ .73), duration of the requirement of ventilatory support (P ‫؍‬ .40), and hospital length of stay (P ‫؍‬ .46) were also comparable between the 2 modes of ventilation. CONCLUSIONS: Compared to NIV-PSV, NIV-NAVA was associated with better patient-ventilator synchrony and a reduction in the number of asynchrony events in subjects with an exacerbation of COPD, with similar effects on improvement in gas exchange, duration of NIV, hospital lenght of stay, and rate of NIV failure. (Clinicaltrials.gov registration NCT02912689.