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Background: We sought to evaluate the institutional use of inhaled nitric oxide (INO) and to create a pathway to reduce waste using the Institute for Healthcare Improvement's model for improvement. Our aim was to reduce the use of INO by 20% within 8 months., Methods: This was a prospective, respiratory therapist-driven, quality improvement project. We implemented a hospital-wide INO utilization protocol that was developed by neonatology, pediatric critical care, cardiac critical care, and respiratory therapy. INO use and respiratory therapist input for protocol failures were derived from the electronic medical record and were used to generate improvement opportunities. Monthly total hospital use of INO (in hours) was used as the primary outcome measure. Median hourly use per subject (evaluated in groups of 7 subjects) was used as a secondary outcome measure. New sildenafil dosing was tabulated for pre- and post-INO weaning protocol intervention as a balancing measure. Subjects included all patients in the hospital who were given INO therapy during the specified timeframe., Results: Hospital-wide total hours were reduced from 1,515 h/month to 930 h/month. This hospital-wide reduction of 39% equates to a cost-avoidance of approximately $912,000 per year based on 2018 costs of INO of $130 per hour. Median hours of INO per subject decreased from 88 h to 50 h. Sildenafil was started in 18 of 98 subjects (18%) in the pre-intervention period and in 12 of 109 subjects (11%) in the post-intervention period ( P = .27)., Conclusions: A hospital-wide, multi-professional initiative led to a reduction in unnecessary INO use, resulting in decreased subject exposure and associated cost avoidance., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2021 by Daedalus Enterprises.)