Atherosclerosis is a systemic, low-grade inflammatory disease affecting large and mid-sized arteries, often in multiple vascular beds. Multisite artery disease (MSAD), also called polyvascular disease (PVD), is defined as the simultaneous presence of clinically relevant atherosclerotic lesions in at least two major vascular beds. In large international registries, MSAD/PVD was found in about a quarter of all patients. In patients presenting with peripheral arterial disease (PAD), coexisting coronary artery disease (CAD) is found in 40–50% of patients, often with accompanying carotid stenosis. The incidence of adverse cardiovascular events increases proportionally with the number of affected vascular beds. However, there is currently no evidence that identification MSAD/PVD in patients with clinically overt atherosclerotic disease, who are already in prevention programs, improves clinical outcomes. On the other hand, detection of atherosclerotic plaques in asymptomatic patients may reclassify cardiovascular risk from intermediate to very high and prompt adequate cardiovascular prevention. All patients with MSAD/PVD should receive lifestyle advice and best medical treatment for the prevention of atherothrombotic events. Revascularization should be performed only in symptomatic vascular beds, using the least aggressive methods according to consensual decisions of multidisciplinary vascular teams.