Background: The possible association between β-adrenoceptor antagonists (β-blockers) and risk of COPD is controversial. The objective of the present study was to test whether β-blocker use is associated with susceptibility to the disease. Methods: A total of 301,542 new users of β-blockers and 1,000,633 new users of any other antihypertensive drugs aged 30–90 years without any history of COPD hospitalizations were included in the present study and followed in the Danish National Patient Registry for incident admissions for COPD and COPD death between 1995 and 2015. Multiple adjusted cox regression models were used to examine the association between use of β-blockers and COPD hospitalization. Additionally, subgroup analyses based on underlying diseases at baseline or duration of treatment were performed. Findings: People treated with β-blockers continuously for more than 6 months had a lower risk of COPD hospitalization during follow-up compared to people treated with any other antihypertensive drugs (adjusted hazard ratio [HRadjusted] 0·80, 95% CI 0·79–0·82). Risk of COPD hospitalization was lowered in the groups treated with β-blockers among patients with ischemic heart disease (0·72, 0·69–0·75), cardiac arrhythmias (0·76, 0·72–0·80), asthma (0·69, 0·61–0·79), hypertension (0·91, 0·86–0·96), and diseases of the pulmonary circulation (pulmonary embolism and cor pulmonale) (0·72, 0·59–0·87). All-cause mortality as well as risk of COPD death during follow-up was lower in the group treated with β-blockers compared to the group treated with any other antihypertensive drugs (0·56, 0·53–0·59). Interpretation: Treatment with β-blockers seems to reduce risk of COPD hospitalization and mortality compared to treatment with any other antihypertensive drugs. Funding: The Danish Council for Independent Research in Denmark (grant no. 4183-00569B), The Research Foundation of Health Science in Region Zealand (grant no. RSSF2017000661 and no. 15-000342), The Research Foundation of Medical Science (A.P. Møller Foundation, grant no. 16-68), The Research Foundation in memory of King Christian 10th (grant no. 142/2017), Aase & Ejnar Danielsen's Research Foundation (grant no. 10-001946), and Lundbeck Foundation (grant no. R252-2017-1690).