Atherosclerosis is a chronic inflammatory disease characterized by the presence of activated immune-competent cells in the lesions, producing mainly proinflammatory cytokines. Atherosclerosis is the underlying cause of cardiovascular disease (CVD), to a large extent occurring after damage and/or rupture of the atherosclerotic plaques. One major factor implicated as a cause of this immune activation is modified low-density lipoproteins (LDL), especially oxidized forms (oxLDL), which are abundant in plaques, both in foam cells and in the necrotic core. The LDL-oxidation process is very complex, and the nature of the antigens has been difficult to identify. We and others have focused on the phospholipids (PL) in oxLDL, especially oxidized forms of PL, including platelet-activating factor (PAF)-like lipids and lysophosphatidylcholine (LPC), and demonstrated that these could play a major role through proinflammatory effects. One common epitope is phosphorylcholine (PC), which is also exposed on some microorganisms (including Streptococcus pneumoneae) and on apoptotic cells. Natural IgM antibodies against PC (anti-PC) have been known for a long time, but little has been reported about their role in human disease, especially in CVD. We have demonstrated that anti-PC IgM are negatively associated with atherosclerosis development in hypertensive individuals and that low levels of anti-PC independently predict development of CVD. Anti-PC IgM could, therefore, be a novel risk marker in CVD. Animal experiments indicate that both active immunization with PC and passive immunization with anti-PC ameliorate atherosclerosis development. The possibility that anti-PC could be used therapeutically in humans deserves further study.