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Purpose: The objective of this study was to assess the clinical and cost benefits of treating patients with chronic obstructive pulmonary disease (COPD) according to global and national guidelines compared to real-life clinical practice in the United States and three European countries (Belgium, Germany, Sweden)., Patients and Methods: A cost-consequence model was developed to compare current prescribing patterns with two alternative scenarios, the first aligned with the Global Initiative for Chronic Obstructive Lung Disease (GOLD 2022) recommendations and the second with national guidelines. Costs and clinical outcomes were modeled for these alternative scenarios over a time horizon of one year, based on real-world evidence and health insurance data., Results: Current clinical practice in each of the countries was inconsistent with published recommendations. A redistribution to prescribing patterns according to global and national recommendations led to a substantial decrease in the use of inhaled corticosteroid (ICS) containing therapies of more than 80% and 44%, respectively. There was a reduced incidence of up to 16% of mild-to-moderate pneumonia and up to 29% of severe pneumonia. Exacerbations decreased across all countries apart from Sweden, where a small increase in the rate of exacerbations was due to the redistribution of some patients currently undergoing inhaled triple therapy to non-ICS-containing therapies. Adapting treatment to recommendations could provide potential cost savings of up to 13% in estimated annual direct costs, resulting predominantly from the reduction in cost of healthcare resource use, including hospitalization associated with treating incident pneumonia, particularly severe pneumonia. Cost savings for prevalent adult patients with COPD on long-acting inhaler therapy ranged from €31 to €675 per patient per year., Conclusion: Redistribution of COPD patients from current clinical practice to treatment according to published recommendations would provide clinical benefits and substantial cost savings., Competing Interests: AW, SL, CW: received consulting fees from Boehringer Ingelheim and are affiliated with Maverex. BC, ESHG, MH: employees of Boehringer Ingelheim. SS reports consulting fees and/or honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Nuvaira, Pulmotect, Aerogen and Cornerstone, grants from Theravance, Regeneron and Sanofi all outside the submitted work. RB reports personal fees from AstraZeneca, Chiesi, Cipla, Sanofi, and Teva, as well as grants and personal fees from Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Roche, all outside the submitted work. The authors report no other conflicts of interest in this work., (© 2022 Sethi et al.)