We previously induced pathogenic antibodies against anionic phospholipids (PL) in experimental animals by immunization with lipid-free purified human β₂glycoprotein I (β₂GPI). We hypothesized that antiphospholipid antibodies (aPL) are induced by in vivo binding of foreign b2GPI to self-PL, thus forming an immunogenic complex against which aPL antibodies are produced. If this hypothesis is true, other PL-binding proteins that are products of ubiquitous viral/bacterial agents may also induce aPL. To test this hypothesis, groups of NIH/Swiss mice were immunized with synthetic peptides of viral and bacterial origin that share structural similarity with the putative PL-binding region of β₂GPI. Compared with the control groups, animals immunized with the peptides produced significantly higher levels of aPL and anti-β₂GPI antibodies. These findings demonstrate that some PL-binding viral and bacterial proteins function like β₂GPI in inducing aPL and anti-β₂GPI production, and are consistent with a role for such viral and bacterial proteins in inducing aPL antibody production in humans.