Background and objective: Acute exacerbations in chronic obstructive pulmonary disease (COPD) may trigger major adverse cardiac events (MACE). We aimed to determine whether the risk of having MACE was transiently increased following the onset of an acute COPD exacerbation. Methods: We conducted a nationwide, register-based study from 1997 to 2014 comprising individuals with an acute COPD exacerbation followed by a MACE (acute myocardial infarction (MI), stroke or cardiovascular death). Using the case-crossover design, we estimated odds ratios (OR) for the association between acute exacerbations of COPD and MACE as well as for single outcomes (acute MI, stroke and cardiovascular death), different levels of severity of exacerbations and within patient subgroups. Results: We identified 118 807 cases with a MACE preceded by an exacerbation. Overall, the risk of MACE increased almost fourfold following the onset of an acute exacerbation compared to periods without exacerbations in the same individuals (OR: 3.70; 95% CI: 3.60–3.80). The associations were consistent for single outcomes (acute MI, OR: 3.57; cardiovascular death, OR: 4.33; and stroke, OR: 2.78) and particularly strong associations were demonstrated for severe exacerbations (OR: 5.92) and the oldest individuals (OR: 4.18). Conclusion: The risk of MACE increased substantially following the onset of an acute exacerbation. This highlights that prevention of cardiac events is an important goal in the management of COPD. Attention should be paid to detecting cardiovascular disease following acute COPD exacerbations.