Observational studies report a reduction of COPD exacerbations in patients treated with β-blockers. In contrast, the Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease (BLOCK COPD) randomised controlled trial which excluded COPD patients with cardiovascular conditions showed an increase in COPD exacerbations. It is unclear whether this discrepancy could be explained by underlying cardiovascular comorbidity. We examined whether the association between use of β-blockers and risk of COPD exacerbations differed between patients with and without a cardiovascular indication for β-blockers use.Within the Rotterdam Study, we followed COPD subjects until the first COPD exacerbation, or end of follow-up. Cardiovascular indication for β-blockers use was defined as a history of hypertension, coronary heart disease, atrial fibrillation and/or heart failure at baseline. The association between β-blockers use and COPD exacerbations was assessed using Cox proportional hazards models adjusted for age, sex, smoking, incident cardiovascular disease (i.e. heart failure, hypertension, atrial fibrillation and/or coronary heart disease during follow-up), respiratory drugs and nitrates.In total, 1312 COPD patients with a mean age of 69.7±9.2 years were included. In patients with a cardiovascular indication (n=755, mean age of 70.4±8.8 years), current use of cardioselective β-blockers was significantly associated with a reduced risk of COPD exacerbations (HR 0.69, 95% CI 0.57–0.85). In contrast, in subjects without a cardiovascular indication (n=557, mean age of 68.8±9.7 years), current use of cardioselective β-blockers was not associated with an altered risk of COPD exacerbations (HR 0.94, 95% CI 0.55–1.62).Use of cardioselective β-blockers reduced the risk of exacerbations in COPD patients with concomitant cardiovascular disease. Therefore, the potential benefits of β-blockers might be confined to COPD patients with cardiovascular disease.