Rationale: Previous studies have suggested that acute exacerbations of COPD may be associated with increased risk of myocardial infarction and ischaemic stroke. Objective: We aimed to quantify the increased risks of myocardial infarction and ischemic stroke risk associated with both moderate and severe acute exacerbation, and to investigate factors which may modify these risks. Methods: We performed a self-controlled case-series to investigate the rates of myocardial infarction and ischemic stroke following acute exacerbation compared to stable time, within individuals. The participants were 5,696 adults with COPD with a first myocardial infarction (n = 2,850) or ischemic stroke (n = 3,010) and at least one acute exacerbation from the UK Clinical Practice Research Datalink with linked Hospital Episodes Statistics data. Results: The risks of both myocardial infarction and ischemic stroke were increased in the 91 days following a acute exacerbation. The risks were greater following a severe exacerbation (incidence rate ratio (IRR) of 2.58 (95% CI 2.26 to 2.95) for myocardial infarction; and IRR 1.97 (95% CI 1.66-2.33) for ischemic stroke) than after a moderate exacerbation (IRR 1.58 (95% CI 1.46-1.71) for myocardial infarction; and IRR 1.45 (95% CI 1.33-1.57) for ischemic stroke. The relative risks of myocardial infarction and ischemic stroke associated with acute exacerbation were lower among those with more frequent exacerbations (IRR 1.42 (95% CI 1.24-1.62) vs 1.69 (95% CI 1.50-1.91) for myocardial infarction; and IRR 1.30 (95% CI 1.15-1.48) vs 1.68 (95% CI 1.50-1.89) for ischemic stroke). Higher GOLD stage associated with a lower rate of myocardial infarction (IRR 1.98 (95% CI 1.61-2.05) vs 1.69 (95% CI 1.45-1.98)) but not for ischemic stroke. Aspirin use at baseline was associated with a lower risk of ischemic stroke (IRR 1.28 (95% CI 1.10-1.50) vs 1.63 (95% CI 1.47-1.80)), but not with myocardial infarction. Conclusions: Acute exacerbations of COPD are associated with an increased risk of myocardial infarction and ischemic stroke within 28 days of their onset. Several patient characteristics were identified which are associated with these events.