beta(2)-glycoprotein I (P(2)GPI) is an absolute requirement for the binding of autoimmune anticardiolipin Abs (aCL) to cardiolipin (CL), We evaluated the target recognition of human beta(2)GPI by IgG derived from two patients with primary and two with secondary antiphospholipid syndrome, The total IgG serum fractions and beta(2)GPI affinity-purified IgGs were assessed by using various domain-deleted mutants (DM) of human beta(2)GPI (DMs: I-III, I-IV, II-V, III-V, IV-V, and V) and mouse mAbs against individual beta(2)GPI domains, The four IgGs bound slightly to CL in the absence of beta(2)GPI and showed increased binding in the beta(2)GPI presence, Following affinity purification of the IgGs on a beta(2)GPI column, reactivity toward CL was absent. DMs containing domain V inhibited the binding of biotinylated beta(2)GPI to CL, The addition to CL-coated plates of DM V, but not the other DMs, reduced the binding of all four IgGs, The anti-beta(2)GPI IgGs bound only to complete beta(2)GPI and DM I-IV coated on the plates, The binding to plate-adsorbed beta(2)GPI could be inhibited by complete beta(2)GPI and DM I-IV, the latter being a more efficient inhibitor, Further, the human anti-beta(2)GPI IgGs could compete with the binding to beta(2)GPI of Cof-21 mouse mAb (directed at domain IV), but not with the two other mouse mAbs, The results suggest that some "autoimmune:" beta(2)GPI-dependent anticardiolipin Abs recognize a beta(2)GPI target that is distinct from the CL-binding site in domain V, The target site for some antiphospholipid syndrome IgGs appear to reside in domain TV of beta(2)GPI.