Evidence has long been lacking that antiendothelial cell (EC) antibodies (AECA) are deleterious, but recent studies have kindled a new debate on their pathogenicity. Intriguingly, they may be associated with infectious diseases and/or with antiphospholipid (PL) antibody (aPL). The latter are directed against complexes of anionic PL, such as phosphatidylserine (PS), and PL-binding cationic proteins, most notably β₂-glycoprotein I (β₂GPI). The mechanism linking the production of pathogenic anti-PL with the presence of AECA is presently unknown. Our hypothesis is that infectious agents generate β₂GPI-independent non-pathogenic anti-PL, and trigger the production of AECA. Some of those encountered in infectious diseases induce EC into apoptosis. They are thus responsible for PS reaching the plasma membrane, a feature for commitment to apoptosis. Defective macrophage clearance of EC undergoing AECA-induced apoptosis prolongs the exposure of PS on their surface, and enables its association with β₂GPI. Owing to this boost by AECA, the infection-induced β₂GPI-independent and non-pathogenic anti-PL are rendered β₂GPI-dependent and pathogenic.