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Background: Eosinophilic chronic rhinosinusitis is an often treatment‐resistant inflammatory disease mediated by type‐2 cytokines, including interleukin (IL)‐5. Mepolizumab, a monoclonal antibody drug targeting IL‐5, has demonstrated efficacy and safety in inflammatory airway disease, but there is negligible evidence on direct tissue response. The study's aim was to determine the local effect of mepolizumab on inflammatory biomarkers in sinonasal tissue of eosinophilic chronic rhinosinusitis patients. Methods: Adult patients with eosinophilic chronic rhinosinusitis received 100mg mepolizumab subcutaneously at four‐weekly intervals for 24 weeks in this prospective phase 2 clinical trial. Tissue eosinophil counts, eosinophil degranulation (assessed as submucosal eosinophil peroxidase deposition by immunohistochemistry) and cytokine levels (measured in homogenates by immunoassay) were evaluated in ethmoid sinus tissue biopsies collected at baseline and at weeks 4, 8, 16 and 24. Results: Twenty patients (47.7 ± 11.7 years, 50% female) were included. Sinonasal tissue eosinophil counts decreased after 24 weeks of treatment with mepolizumab (101.64 ± 93.80 vs 41.74 ± 53.76 cells per 0.1 mm2; p =.035), eosinophil degranulation remained unchanged (5.79 ± 2.08 vs 6.07 ± 1.20, p =.662), and type‐2 cytokine levels increased in sinonasal tissue for IL‐5 (10.84 ± 18.65 vs 63.98 ± 50.66, p =.001), IL‐4 (4.48 ± 3.77 vs 9.38 ± 7.56, p =.004), IL‐13 (4.02 ± 2.57 vs 6.46 ± 3.99, p =.024) and GM‐CSF (1.51 ± 1.74 vs 4.50 ± 2.97, p =.001). Conclusion: Mepolizumab reduced eosinophils in sinonasal tissue, demonstrating that antagonism of IL‐5 suppresses eosinophil trafficking. With reduced tissue eosinophils, a local type‐2 inflammatory feedback loop may occur. The study exposes mechanistic factors which may explain incomplete treatment response. [ABSTRACT FROM AUTHOR]