Summary. Aims: Atherosclerosis is the most frequent cause of coronary artery disease (CAD), cerebrovascular disease (CVD), and peripheral arterial obstructive disease (PAD). We previously found that patients with CVD or PAD had a two-fold higher risk of major hemorrhagic complications than patients with CAD. We investigated whether this difference was attributable to baseline risk factors or genetic variants involved in hemostasis. Methods and results: We included 2622 consecutive patients from a single university hospital who presented with non-disabling CAD, CVD, or PAD. All patients were followed for the occurrence of major hemorrhagic complications for a mean of 6.6 years. Major hemorrhagic events included intracranial hemorrhagic events, fatal hemorrhagic events, and any hemorrhagic complications requiring hospitalization, irrespective of interventions. Major hemorrhagic complications occurred in 122 patients (annual event rate of 0.77%). Patients with CVD or PAD had more hemorrhagic complications than patients with CAD (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.39–3.01). Hypertension, diabetes, renal failure and use of oral anticoagulants or antiplatelet therapy did not explain the difference (HR adjusted for all characteristics 1.74; 95% CI 1.14–2.61). Additional adjustment for genetic variants did not further change the HR. Conclusion: Patients with CVD or PAD are at higher risk for major hemorrhagic events than patients with CAD. This difference could not be explained by known risk factors, use of antithrombotic agents, or genetic variants involved in hemostasis. Further research to find the reason for this difference and possible differences in pathogenesis is warranted.