Background: Beta-blockers have been proposed to improve COPD-related outcomes, yet studies report conflicting results. We aimed to investigate the effect of beta blockers on time-to-first exacerbation and all-cause mortality in high-risk COPD outpatients. Methods: All COPD outpatients managed at the Department of Respiratory Medicine, Copenhagen University Hospital – Hvidovre, Denmark in 2016 were followed for 3.5 years in this retrospective, registry-based cohort study. Outcomes were time-to-first acute exacerbation of COPD (AECOPD) or death. The association was estimated using time-varying crude and multivariable Cox proportional hazard regression adjusted for age, sex, BMI, use of COPD medication, smoking status, cardiovascular disease and COPD severity. Results: The cohort comprised 950 COPD outpatients, mean age 71 (SD 11) years, and FEV₁ 44% predicted (IQR 33%; 57%). The annual exacerbation rate was 0.88 (SD 1.68) and 211 patients (22%) had a history of hospitalization requiring AECOPD within 12 months. Of the enrolled patients, 247 (26%) were prescribed beta blockers. Beta-blocker use was associated, although with borderline significance, with increased all-cause mortality (HR 1.37 (95% CI, 0.99 to 1.89, p = 0.059)). On the other hand, beta blocker use did not reduce the risk of AECOPD (HR = 0.89 (95% CI 0.71 to 1.10; p = 0.270)), which remained non-significant after stratifying for severity of exacerbations. Conclusion: We found an association between beta blocker use and all-cause mortality in high-risk COPD outpatients. No association was found between beta blocker use and risk of AECOPD.