Rationale: Accumulation of eosinophils in the bronchial mucosa of individuals with asthma is considered to be a central event in the pathogenesis of asthma. In animal models, airway eosinophil recruitment and airway hyper-responsiveness in response to allergen challenge are reduced by specific targeting of interleukin-5. A previous small dose-finding study found that mepolizumab, a humanized anti-interleukin-5 monoclonal antibody, had no effect on allergen challenge in humans. Objective: To investigate the effect of three intravenous infusions of mepolizumab 250 mg or 750 mg at monthly intervals on clinical outcome measures in 362 patients with asthma experiencing persistent symptoms despite inhaled corticosteroid therapy (400-1000 µg beclomethasone or equivalent). Method: Multicenter, randomized, double-blind, placebo-controlled study. Measures: Morning peak expiratory flow, forced expiratory volume in 1 second, daily ₂-agonist use, symptom scores, exacerbation rates and quality of life measures. Sputum eosinophil levels were also measured in a subgroup of 37 individuals. Main results: Mepolizumab was associated with a significant reduction in blood and sputum eosinophils in both treatment groups (blood: p<0.001 for both doses; sputum: p=0.006 for 250 mg and p=0.004 for 750 mg). There were no statistically significant changes in any of the clinical endpoints measured. There was a non-significant trend for decrease in exacerbation rates in the mepolizumab 750 mg treatment group (p=0.065). Conclusions: Mepolizumab treatment does not appear to add significant clinical benefit in asthmatic patients with persistent symptoms despite inhaled corticosteroid therapy. Further studies are needed to investigate the effect of mepolizumab on exacerbation rates using protocols specifically tailored to asthmatics with persistent airway eosinophilia.