Severe asthma is a high burden disease. Real-world data on mepolizumab in patients with severe eosinophilic asthma is needed to assess whether the data from randomised controlled trials are applicable in a broader population.The Australian Mepolizumab Registry (AMR) was established with an aim to assess the use, effectiveness and safety of mepolizumab for severe eosinophilic asthma in Australia.Patients (n=309) with severe eosinophilic asthma (median age 60years, 58% female) commenced mepolizumab. They had poor symptom control [median Asthma Control Questionnaire (ACQ)-5 score of 3.4], frequent exacerbations [median 3 courses of oral corticosteroids (OCS) in the previous 12months], and 47% required daily OCS. Median baseline peripheral blood eosinophil level was 590cellsL-1 Comorbidities were common: allergic rhinitis 63%, gastro-oesophageal reflux disease 52%, obesity 46%, nasal polyps 34%.Mepolizumab treatment reduced exacerbations requiring OCS compared to the previous year (annualised rate ratio 0.34 [95% CI 0.29-0.41], p<0.001) and hospitalisations (rate ratio 0.46 [95% CI 0.33-0.63], p<0.001). Treatment improved symptom control (median ACQ-5 reduced by 2.0 at 6months), quality of life and lung function. Higher blood eosinophil levels (p=0.003) and later age of asthma onset (p=0.028) predicted a better ACQ-5 response to mepolizumab, whilst being male (p=0.031) or having body mass index 30 (p=0.043) predicted a lesser response. Super-responders (upper 25% of ACQ-5 responders, n=61, 24%) had a higher T2 disease burden and fewer comorbidities at baseline.Mepolizumab therapy effectively reduces the significant and long-standing disease burden faced by patients with severe eosinophilic asthma in a real-world setting.