Objective— The objective of this present study is to determine whether high ankle brachial index (ABI) as compared with ABIs within reference limits is associated with an increased incidence of cardiovascular disease (CVD) events and all-cause mortality in a high-risk population and whether this association is the same for patients with and without diabetes mellitus or prevalent CVD. Approach and Results— Seven thousand five hundred and thirty-eight patients with ABI>0.9 and either prevalent CVD or a high risk for CVD were selected from the Second Manifestations of Arterial Disease (SMART) study. Three hundred and thirty-six participants (4.5%) had high ABI (≥1.4 or incompressible). Higher age, male sex, higher body mass index, and diabetes mellitus were associated with higher prevalences of high ABI; smoking and higher non–high-density lipoprotein levels were associated with lower prevalences of high ABI. Cox proportional hazards models were fitted assessing the association of high ABI (as compared with ABI 0.9–1.4) with the risk of myocardial infarction, stroke, cardiovascular death, the combined outcome of these 3, and total mortality (median follow-up 6.9 years). After multivariable adjustment, high ABI was associated with an increased risk of myocardial infarction (hazard ratio 1.83 [95% confidence interval 1.22–2.76]), but not with stroke (hazard ratio 0.86 [95% confidence interval 0.44–1.69]), cardiovascular (hazard ratio 1.14 [95% confidence interval 0.70–1.84]), or all-cause mortality (hazard ratio 0.95 [95% confidence interval 0.67–1.34]). Associations of high ABI with CVD outcomes tended to be stronger in patients with diabetes mellitus but without statistically significant interactions. Conclusions— In a high-risk population, the presence of an ABI≥1.4 was associated with an increased risk for myocardial infarction, but not with stroke, all-cause, or vascular mortality.