Objective Exacerbations and suboptimal disease control are common in severe asthma with an eosinophilic phenotype (SAep). Mepolizumab, an anti-interleukin-5 monoclonal antibody, has demonstrated efficacy and safety in randomized controlled trials (RCTs). We aimed to strengthen the real-world evidence base for mepolizumab in SAep.Methods We analyzed data from Italian participants of REALITI-A, a global, real-world, prospective, observational study (primary outcome: rate of clinically significant exacerbations [CSEs]). Using these data and those from Italian real-world studies of mepolizumab (identified by systematic literature review), we performed a meta-analysis.Results In the Italian cohort of REALITI-A (n = 244), mean CSE rate was lower 12 months post-mepolizumab initiation versus 12 months pre-mepolizumab (0.67 vs 3.74 CSEs/patient/year; relative risk [RR], 0.18; 95% confidence interval (CI), 0.15-0.22; P < .001). The meta-analysis included 863 patients. Mean CSE rate decreased from 4.2/patient/year at baseline to 0.71/patient/year post-mepolizumab initiation. Mean oral corticosteroid (OCS) dose reduced by 8.66 mg/day (95% CI, 6.17-11.16 mg/day; P < .0001) from baseline (10.0 mg/day). The RR for OCS maintenance, post- versus pre-mepolizumab, was 0.37 (95% CI, 0.27-0.52; P < .0001). A mean increase in Asthma Control Test score of 6.50 (95% CI, 5.67-7.33; P < .00001) was observed. Proportions of patients reporting adverse events were low.Conclusions Real-world experience in this unified health care system identifies that mepolizumab has a low adverse event rate and provides consistent clinical benefits. Mepolizumab represents an important treatment option for patients with SAep.