Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease with no approved treatment in the United States. Dupilumab, a VelocImmune-derived human monoclonal antibody against the interleukin 4 (IL4) receptor, inhibits IL4 and IL13 signaling. Dupilumab is effective in treatment of allergic, atopic, and type 2 diseases, so we assessed its efficacy and safety in patients with EoE.We performed a phase 2 study of adults with active EoE (2 dysphagia episodes of dysphagia/week with peak esophageal eosinophil density of 15 or more eosinophils per high-power field), from May 12, 2015 through November 9, 2016 at 14 sites. Subjects were randomly assigned to groups that received weekly subcutaneous injections of dupilumab (300 mg; n=23) or placebo (n=24) for 12 weeks. The primary endpoint was change from baseline to week 10 in Straumann dysphagia instrument patient-reported outcome (SDI-PRO) score. We also assessed histologic features of EoE (peak esophageal intraepithelial eosinophil count and EoE histologic scores), endoscopically visualized features (endoscopic reference score), esophageal distensibility, and safety.The mean SDI-PRO score was 6.4 when the study began. In the dupilumab group, SDI-PRO scores were reduced by a mean value of 3.0 at week 10 compared with vs a mean reduction of 1.3 in the placebo group (P=.0304) At week 12, dupilumab reduced peak esophageal intraepithelial eosinophil count by a mean 86.8 eosinophils per high-power field (reduction of 107.1%; P<.0001 compared with baseline), the EoE-HSS severity score by 68.3% (P<.0001 vs baseline), and the endoscopic reference score by 1.6 (P=.0006 compared with baseline. Dupilumab increased esophageal distensibility by 18% compared with baseline (P<.0001). Higher proportions of patients in the dupilumab group developed injection-site erythema (35% vs 8% in the placebo group) and nasopharyngitis (17% vs 4% in the placebo group).In a phase 2 trial of patients with active EoE, dupilumab reduced dysphagia, histologic features of disease (including eosinophilic infiltration and a marker of type 2 inflammation), and abnormal endoscopic features, compared with placebo. Dupilumab increased esophageal distensibility and was generally well tolerated. ClinicalTrials.gov no: NCT02379052.