BACKGROUND: Despite the availability of effective treatments, patients with asthma, regardless of severity, remain at risk of severe exacerbations resulting in significant burden to patients, the health care system, and insurance providers. OBJECTIVE: To examine severe exacerbations, treatment patterns, health care resource utilization (HCRU), and costs across all asthma severities. METHODS: In this retrospective study, patients aged 4 years and older filling 1 short-acting (β2-agonist (SABA) and at least 1 maintenance fill or at least 2 SABAs with or without maintenance fills were identified from administrative claims data from the IBM MarketScan Commercial and IBM MarketScan Multistate Medicaid Research databases (January 2010 to December 2017). Patients were indexed on a random SABA fill (2011-2016) and had 12 months of continuous eligibility pre-index and post-index. Patients were classified into Global Initiative for Asthma (GINA) 2018 severity steps and by asthma control, as measured by SABA fill use in the 12 months pre-index: low (1 SABA fill per year), medium (2-3 SABA fills per year), and high (≥ 4 SABA fills per year); well controlled, not well controlled, and very poorly controlled, respectively. Severe asthma exacerbation events, health care costs, and asthma-related HCRU and costs were assessed relative to asthma severity and asthma control post-index. RESULTS: Of 1,005,522 patients, 50.3% filled GINA Step 1; 19.7% GINA Step 2; 10.9% GINA Step 3; and 19.1% GINA Steps 4-5 treatments. Overall, 953,337 severe exacerbation events occurred (approximately 0.95 events per patient), equating to 0.96, 0.67, 0.83, and 1.28 events per patient for patients filling GINA Step 1 through Steps 4-5, respectively. GINA Step 1 had the highest proportion of patients experiencing at least 1 event (57.0%), followed by GINA Steps 4-5 (55.2%), GINA Step 3 (45.0%), and GINA Step 2 (41.9%) treatments (P < 0.05). For GINA Step 1, 64.4% of well-controlled patients experienced at least 1 exacerbation event vs 50.4% of not well-controlled and 53.0% of very poorly controlled patients (P < 0.05). For patients filling GINA Step 2-5 treatments, a greater proportion of very poorly controlled patients experienced at least 1 exacerbation event vs well-controlled patients (P < 0.05). The average total annual health care cost per patient was $7,148 and total annual asthma-related costs were $1,741. Each additional SABA fill was associated with a 26.0%, 10.8%, and 34.6% increase in incidence of total exacerbations, all-cause costs, and asthma-related costs, respectively (P < 0.05). CONCLUSIONS: In this real-world database study, increased SABA fills and occurrence of exacerbations were correlated and associated with higher all-cause and asthma-related costs across all severities. New treatment paradigms, particularly for rescue therapies, are warranted to improve clinical and cost outcomes in these patients. DISCLOSURES: This analysis was funded by AstraZeneca. Michael Pollack, Hitesh Gandhi, and Ileen Gilbert are employees and stockholders of AstraZeneca and contributed to the design and conduct of the study. AstraZeneca was given an opportunity to review the final version of the manuscript. At the time of the study, Joseph Tkacz was an employee of IBM Watson Health, which received funding from AstraZeneca to conduct this study. Miguel Lanz has received research funding from AstraZeneca, Optinose, and Regeneron and consulting fees and honoraria from ALK, Amgen, AstraZeneca, Novartis, Sanofi, and Regeneron. Njira Lugogo received consulting fees for advisory board participation from Amgen, AstraZeneca, Genentech, GlaxoSmith-Kline, Novartis, Regeneron, Sanofi, and Teva; honoraria for nonspeaker's bureau presentations from GlaxoSmithKline and AstraZeneca; and travel support from AstraZeneca. Her institution received research support from Amgen, AstraZeneca, Avillion, Gossamer Bio, Genentech, GlaxoSmithKline, Regeneron, Sanofi, and Teva.