IMPORTANCE Dupilumab has demonstrated efficacy in patients with asthma and atopic dermatitis, which are both type 2 helper T-cell-mediated diseases. OBJECTIVE To assess inhibition of interleukins 4 and 13 with dupilumab in patients with chronic sinusitis and nasal polyposis. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled parallel-group study conducted at 13 sites in the United States and Europe between August 2013 and August 2014 in 60 adults with chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids with 16 weeks of follow-up. INTERVENTIONS Subcutaneous dupilumab (a 600mg loading dose followed by 300mg weekly; n = 30) or placebo (n = 30) plus mometasone furoate nasal spray for 16 weeks. MAIN OUTCOMES AND MEASURES Change in endoscopic nasal polyp score (range, 0-8; higher scores indicate worse status) at 16 weeks (primary end point). Secondary end points included Lund-Mackay computed tomography (CT) score (range, 0-24; higher scores indicate worse status), 22-item SinoNasal Outcome Test score (range, 0-110; higher scores indicating worse quality of life; minimal clinically important difference≥8.90), sense of smell assessed using the University of Pennsylvania Smell Identification Test (UPSIT) score (range, 0-40; higher scores indicate better status), symptoms, and safety. RESULTS Among the 60patients whowere randomized (mean [SD] age, 48.4 years [9.4 years]; 34 men [56.7%]; 35 with comorbid asthma), 51 completed the study. The least squares (LS) mean change in nasal polyp scorewas-0.3 (95%CI,-1.0to 0.4) with placebo and-1.9 (95%CI,-2.5 to-1.2) with dupilumab (LS mean difference,-1.6 [95%CI,-2.4 to-0.7]; P < .001). The LS mean difference between the 2 groups for the Lund-Mackay CT total scorewas-8.8 (95%CI,-11.1 to-6.6; P < .001). Significant improvements with dupilumabwere also observed for the 22-item SinoNasal Outcome Test (LS mean difference between groups,-18.1 [95%CI,-25.6 to-10.6]; P < .001) and sense of smell assessed by UPSIT (LS mean difference, 14.8 [95%CI, 10.9 to 18.7]; P < .001). The most common adverse eventswere nasopharyngitis (33%in the placebo group vs 47% in the dupilumab group), injection site reactions (7%vs 40%, respectively), and headache (17%vs 20%). CONCLUSIONS AND RELEVANCE Among adults with symptomatic chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids, the addition of subcutaneous dupilumab to mometasone furoate nasal spray compared with mometasone alone reduced endoscopic nasal polyp burden after 16 weeks. Further studies are needed to assess longer treatment duration, larger samples, and direct comparison with other medications.