OBJECTIVE: Although the efficacy of mepolizumab in reducing exacerbations and oral corticosteroid (OCS) use in severe asthma is well-established, real-world long-term effectiveness data are limited. This study evaluated the real-world impact of mepolizumab treatment in patients with severe asthma over a 4-year follow-up period. METHODS: This was a retrospective cohort study of patients with asthma initiating mepolizumab (index date: first claim, November 2015-September 2019) using the Merative MarketScan Commercial and Medicare Databases. Outcomes included asthma exacerbations, OCS use, and exacerbation-related healthcare resource utilization (HCRU) and costs, assessed 12-months pre-index (baseline) and annually during the 4-year follow-up period. RESULTS: Among 189 eligible patients, mean asthma exacerbation rate (AER) declined progressively from baseline during follow-up: AER decreased by 53.8% at Year 1 and 73.8% by Year 4 ( CONCLUSION: Patients treated with mepolizumab demonstrated progressive and sustained long-term, real-world reductions in exacerbation frequency, OCS dependency, and exacerbation-related HCRU and costs over 4 years.