beta(2)-glycoprotein I (beta(2)GPI) is the major antigenic target for antiphospholipid Abs. Anti-beta(2)GPI Abs are a heterogeneous population of Igs targeting all domains of the molecule. Abs specific to beta(2)GPI domain I are strongly associated with thrombosis and obstetric complications. In the present study, we sought to understand the possible pathogenic mechanism for this subset of anti-beta(2)GPI Abs, investigating their potential cross-reactivity with other self-proteins involved in inflammatory or coagulant events. We compared the amino acid sequence of the beta(2)GPI domain I with human proteins in a protein databank and identified a peptide sharing 88% identity with an epitope of human TLR4. A high percentage of patients with antiphospholipid syndrome (41%) and systemic lupus erythematosus (50%) presented serum IgG specific to this peptide. Anti-beta(2)GPI peptide Abs binding the TLR4 were able to induce NF-kappa B activation in HEK293 cells that were stably transfected with the TLR4 gene. Anti-beta(2)GPI peptide Abs induced activation of TLR4 and triggered interleukin-1 receptor-associated kinase phosphorylation and NF-kappa B translocation, promoting VCAM expression on endothelial cells and TNF-alpha release by monocytes. In conclusion, our observations suggest a novel pathogenic mechanism in the TLR4 stimulation by anti-beta(2)GPI peptide Abs that links adaptive immune responses with innate immunity in antiphospholipid syndrome and systemic lupus erythematosus. (Blood. 2012;120(16):3360-3370)