Antiphospholipid syndrome (APS) is the most common cause of acquired thrombophilia, but experimental and clinical evidence accumulated over the years suggest that the clinical manifestations of APS go beyond those of a simple hypercoagulable state. Although still a controversial topic, the elevated risk of atherosclerosis in systemic lupus erythematosus seems little accounted for by the presence of antiphospholipid antibodies, whereas premature atherosclerosis has been addressed in few series of patients with primary APS. The available data in primary APS suggest that traditional risk factors for atherosclerosis are less involved in arterial disease, rather antiphospholipid antibodies appear as major players. Their effect on the coagulation system, the vessel wall and on the antioxidant/oxidant balance impairs vascular homeostasis, leading to premature arterial thickening.