Purpose: Mepolizumab is a human monoclonal antibody against interleukin 5 (IL-5) used to treat severe eosinophilic asthma. Several studies have evaluated the effectiveness of mepolizumab in the real world. We conducted a systematic review and meta-analysis in the context of heterogeneity among patients, clinicians, and treatment regimens to study the effectiveness of mepolizumab in the real world. Methods: We searched the PubMed and Embase databases for real-world studies on severe asthma treatment with mepolizumab as of June 30, 2020. Exacerbations, asthma-related hospitalizations, forced expiratory volume in 1 second (FEVi ), Asthma Control Questionnaire (ACQ) or Asthma Control Test (ACT), corticosteroid use, peripheral blood eosinophil counts, and the fraction of exhaled nitric oxide were selected as indicators to evaluate the effectiveness. Standardized mean differences by the Cohen method and mean differences were chosen as indicators of effect size. Cohen d values of 0.2, 0.5, and 0.8 are considered as small, medium, and large effects, respectively. We used the Dersimonian-Laird random-effect model to quantify pooled effectiveness estimates. Findings: A total of 1457 patients from 13 studies were included in this review. At all time points, mepolizumab was associated with reductions in exacerbations (2.92 and 2.73 events per patient per year fewer at 6 and 12 months, respectively) and hospitalizations (0.36 events per patient per year fewer at 12 months); improvements in asthma control (ACQ scores reductions of 1.32 and 1.03 at 6 and 12 months, respectively; ACT scores increase of 6.52 at 6-12 months); slight improvements in pulmonary function (FEV1 increase of 0.23 L at 1-3 months and 6-12 months, respectively); reductions in oral corticosteroid use (9.02- and 7.68-mg decrease at 6 and 12 months, respectively); and reductions in peripheral blood eosinophil counts (decreases of 559.11 cells/mu L and 599.17 cells/mu L at 1-3 months and 6-12 months, respectively) and fraction of exhaled nitric oxide (13-ppb reduction at 6-12 months). (C) 2021 Published by Elsevier Inc.