Although during the last decade there have been great advances in our knowledge of the epidemiology and pathophysiology of multi-district atherosclerotic disease, little is known about the association between peripheral arterial disease and carotid artery disease. This review was conceived to cast some light on this topic, paying special attention to inflammation which plays a pivotal role in atherosclerosis. An aspect of pathophysiologic and clinical relevance is that the coexistence of carotid disease is more frequent in peripheral arterial disease than in coronary artery disease, not only in terms of carotid stenosis, but also with respect to the presence of hypoechoic unstable plaque. These latter plaques present a large infiltration of macrophages and are associated to high levels of inflammatory markers. In particular, the greater prevalence of hypoechoic carotid plaques in peripheral arterial disease compared to patients with carotid artery disease was poorly related to classic risk factors, but showed an independent association with an increased number of leukocyte and neutrophil cells, which are reliable markers of inflammation. The greater prevalence of hypoechoic unstable carotid plaques could explain why peripheral arterial disease portends higher risk of stroke than coronary artery disease.