Factor XIII (FXIII) is a protransglutaminase that, after activation, cross-links fibrin chains and several plasma proteins, most importantly alpha (2) plasmin inhibitor, to fibrin. FXIII strengthens the fibrin clot by covalent bonds and protects fibrin from the prompt elimination by the fibrinolytic system. In the last two decades, FXIII has emerged as a key regulator of fibrinolysis. FXIII is also present in platelets, monocytes, and macrophages, but this cellular form does not contribute significantly to maintaining hemostasis. FXIII deficiency is a life-threatening bleeding diathesis whose clinical consequences are well studied. In contrast, the involvement of FXIII in thrombotic disorders and its association with the risk of such diseases are less clear. This review gives an account of the data accumulated mainly in the last decade on the association of FXIII with atherothrombotic diseases and presents conclusions and hypotheses drawn from these data as well as exposing the limitations of the published studies and our knowledge on this topic. The involvement of FXIII in atherogenesis, its role in coronary artery disease, atherothrombotic ischemic stroke, and peripheral artery disease are discussed, with particular reference to the association of FXIII levels and polymorphisms with the risk of these diseases.