Background: In controlled clinical studies, mepolizumab has been shown to reduce exacerbation rates and the use of oral corticosteroids as well as improve asthma control and health-related quality of life compared with placebo in patients with severe eosinophilic asthma. However, real-world data on the impact of mepolizumab on clinical outcomes are limited. Objective: To evaluate the effect of mepolizumab on asthma exacerbations and asthma exacerbation-related costs in patients with severe asthma in U.S. clinical practice. Methods: This retrospective cohort study used U.S. administrative claims data from patients ages ≥12 years and with severe asthma at mepolizumab treatment initiation (index date; identification period, January 2015-June 2017) who had received two or more mepolizumab administrations within 180 days of the index date and had no evidence of treatment with another asthma biologic. The exacerbation rate and exacerbation-related costs were assessed in both the 12 months before mepolizumab initiation (baseline period) and the following 12 months (follow-up period). A clinical trial-like cohort was identified, defined as patients with two or more baseline exacerbations and ≥10 administrations during follow-up. Results: A total of 201 patients were included in the overall population and 74 patients in the clinical trial-like cohort. Mepolizumab significantly reduced the exacerbation rate between the baseline and follow-up periods in both the overall population and the clinical trial-like cohort (p < 0.001), which corresponded to 33.6% and 48.6% reductions, respectively. The rate of exacerbations in patients who required hospitalization between the baseline and follow-up periods was also reduced by 35.3% (p = 0.080) and 68.2% (p = 0.015) in the overall population and in the clinical trial-like cohort, respectively. Cost data were inconclusive. Conclusion: This study, which used real-world data, demonstrated that mepolizumab is associated with reductions in asthma exacerbations, in line with the findings from controlled clinical studies. These results provided further evidence of the effectiveness of mepolizumab in a real-world setting.