OBJECTIVE To investigate the clinical efficacy and safety of dupilumab in patients with severe asthma-chronic obstructive pulmonary disease （COPD） overlap （ACO）. METHODS A retrospective analysis was conducted on 150 patients with severe ACO treated at Nantong Third People’s Hospital during Jan. 2022-Dec. 2023. Patients were divided into the control group [conventional therapy with inhaled corticosteroids （ICS）+long-acting beta-2 agonists （LABA）+long-acting muscarinic anticholinergic （LAMA）， n＝90] and the observation group （conventional therapy plus dupilumab， n＝60） based on different treatment regimens. Propensity score matching （PSM） was performed at a ratio of 1.5∶1. Symptom control scores [Asthma Control Test （ACT） score， COPD Assessment Test （CAT） score] and pulmonary function parameters [forced vital capacity （FVC）， forced expiratory volume in 1 second （FEV1）， the FEV1 in percentage of predicted value （FEV1%pred）， the ratio of FEV1 and FVC （FEV1/FVC）， peak expiratory flow （PEF） and maximal mid-expiratory flow （MMEF）] before treatment and at 1， 3， and 12 months after treatment， as well as the levels of biomarkers [peripheral blood eosinophil （EOS） count， immunoglobulin E （IgE）， C-reactive protein （CRP）， fractional exhaled nitric oxide （FeNO）]， annual acute exacerbation frequency， quality-of-life scores [Asthma Quality of Life Questionnaire （AQLQ） score， St George’s Respiratory Questionnaire （SGRQ） score， and Medical Outcomes Study 36-item Short Form Health Survey （SF-36） score] before treatment and 12 months after treatment， and the occurrence of adverse reactions were compared. RESULTS After PSM， 120 patients were included， involving 72 cases in the control group and 48 cases in the observation group. Compared with before treatment， both groups showed significant improvements in ACT scores at 1， 3， and 12 months after treatment， FVC， FEV1， FEV1%pred （except at 3 months after treatment in the control group）， （except at 3 months after treatment in the control group）， PEF （except at 3 and 12 months after treatment in the control group） and MMEF （including at 1 month after treatment in the observation group） at 3 and 12 months after treatment， as well as AQLQ and SF-36 scores at 12 months after treatment （P＜0.05）. CAT scores at 1， 3 and 12 months after treatment， annual acute exacerbation frequency and SGRQ score at 12 months after treatment， FeNO levels at 12 months after treatment in the control group， as well as EOS count， IgE， CRP and FeNO levels at 12 months after treatment in the observation group were significantly reduced （P＜0.05）. The improvements of above indicators in the observation group were mostly greater than in the control group （P＜0.05）. The incidence of adverse reactions did not differ significantly between the two groups （P＞0.05）. CONCLUSIONS Dupilumab provides superior efficacy over conventional therapy in improving clinical symptoms， pulmonary function， and quality of life， while reducing biomarker levels in patients with severe ACO， with a comparable safety profile to standard therapy.