Rationale: Dupilumab, a fully human VelocImmune®-derived anti-interleukin (IL)-4 receptor α monoclonal antibody, inhibits IL-4/IL-13 signaling pathways, key drivers of type 2 inflammation. Dupilumab is approved for the treatment of inadequately controlled, moderate-to-severe atopic dermatitis and, in the USA, for patients aged ≥12 years with moderate-to severe eosinophilic or corticosteroid-dependent asthma. In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), dupilumab 200mg and 300mg every 2 weeks (q2w) significantly reduced annualized severe exacerbation rates, improved pre-bronchodilator FEV1, and improved quality-of-life measures vs placebo in the overall population of patients with uncontrolled, moderate-to-severe asthma. Treatment effects were greater in patients with elevated type 2 biomarkers at baseline (blood eosinophils ≥150 cells/µL or FeNO ≥25 ppb). Recurrent severe asthma exacerbations lead to loss of lung function. This post hoc analysis assessed the effect of dupilumab on lung function by number of exacerbations during the randomized study period. Methods: LS mean change from baseline in pre- and post-bronchodilator FEV1 at Week 52, adjusted for baseline FEV1, was assessed in patients experiencing 0, 1, 2, and ≥3 exacerbations during the study period receiving dupilumab 200mg or 300mg q2w or matched placebo. Results: Baseline characteristics were generally similar; levels of type 2 biomarkers were higher in the placebo group in patients with 0 exacerbations during the study period. A greater proportion of dupilumab-treated patients vs placebo had 0 exacerbations during the study period. Dupilumab 200mg/300mg q2w significantly (P<0.001) improved LS mean difference (95% CI) in change from baseline post-bronchodilator FEV1 by 0.20L (0.13-0.26)/0.13L (0.06-0.20) vs placebo (Figure) in patients experiencing 0 exacerbations during the study period. LS mean difference in change from baseline post-bronchodilator FEV1 was 0.14L (0.02-0.26)/0.01L (−0.11-0.14), 0.12L (−0.08-0.32)/0.10L (−0.09-0.30), and 0.12L (−0.14-0.37)/0.13L (−0.09-0.35) in patients experiencing 1, 2, and ≥3 exacerbations during the study period, respectively, comparing dupilumab to placebo. Similar trends were observed with pre-bronchodilator FEV1 at Week 52. The most frequent adverse event in dupilumab-treated groups vs placebo was injection site reactions (15%/18% vs 5%/10%). Conclusions: Most patients on dupilumab did not experience an exacerbation during the study period. In patients experiencing exacerbations during the study period, lung function worsened with increasing number of exacerbations in placebo groups. In contrast, dupilumab-treated patients consistently improved post-bronchodilator FEV1, though the magnitude of improvements diminished with increasing number of exacerbations. These data highlight the important relationship between exacerbation avoidance and lung function preservation in moderate-to-severe asthma.