Abstract Background: Patients with refractory chronic cough (RCC) with underlying asthma or non-asthmatic eosinophilic bronchitis (NAEB) often have persistent elevated airway eosinophils and coughing despite inhaled or oral corticosteroid (ICS/OCS). Eosinophils have been found to be co-localised with sensory airway nerves, and after allergen challenge, have been shown to be associated with increased neuronal sensitivity. We evaluated whether mepolizumab, a monoclonal antibody targeting interleukin-5, reduces coughs in RCC with asthma or NAEB and elevated sputum eosinophilia who have not responded to ICS therapy. Methods: We conducted a randomized, double-blind, placebo-controlled, parallel-group trial of 30 patients with RCC and eosinophilic airways disease (defined as sputum eosinophilia ≥2% with either asthma or NAEB). Patients underwent 1:1 randomization to receive either 4 doses of subcutaneous mepolizumab (100 mg) or placebo every 4 weeks. The primary endpoint was the change from baseline 24-hour cough frequency (c/hr) at week 14 using the VitaloJAK cough monitor. Secondary endpoints included change from baseline in awake and night-time cough frequency (c/hr) measured at weeks 8 and 14, quality of life on the Leicester Cough Questionnaire (LCQ), and cough severity Visual Analogue Scale (VAS, 0-100mm) measured at weeks 4, 8, 12 and 14 post randomization. Safety was also evaluated. Generalized estimating equations were used to generate estimated marginal means for geometric mean cough frequency at weeks 0, 8 and 14 post randomization adjusted for age, sex, and log baseline cough frequency (c/hr). Results:46 participants with RCC were recruited and 30 met eligibility who were randomised (mean age (S.D.) 65.8 (11.6), 56.7% female, % sputum eosinophils 3.7% (2.4), 19 asthma, 11 NAEB). Treatment with mepolizumab did not result in a significant reduction in 24-hour cough frequency compared with placebo at week 14 (percentage change 18.6%, 95% C.I. (-23% to 82%) (P = 0.44) (Figure 1). There was also no difference between awake and night-time objective cough frequencies, LCQ, or cough severity VAS. Mepolizumab did significantly lower absolute blood eosinophil count (P < 0.001). There were no serious adverse events. Conclusion: In patients with RCC secondary to asthma or NAEB with elevated sputum eosinophilia, mepolizumab did not objectively or subjectively improve cough despite reductions in blood eosinophils. Targeting eosinophils might not improve coughs and an alternative mechanism might be driving cough in this RCC group. (Funded by an investigator-initiated grant from GlaxoSmithKline; ClinicalTrials.govNCT04765722.)