beta 2glycoprotein I (beta 2GPI) is a phospholipid-binding protein of the coagulation system. In patients with the antiphospholipid syndrome (APS), antibodies to beta 2GPI contribute to the population of "antiphospholipid antibodies" measured in the anticardiolipin antibody (aCL) assay. In fact, both IgG and IgM antibodies from patients with APS bind beta 2GPI in the absence of anionic phospholipids if the antigen is bound to a suitable surface, i.e., one which exposes the epitope. The binding of IgA was studied from patients with APS, using an enzyme-linked immunosorbent assay (ELISA), and significantly higher binding of IgA was observed from 39 patients compared to a control group of 50 healthy individuals (p < 0.0001). Moreover, 15 out of 39 APS subjects (38 percent) exhibited binding greater than 5 standard deviations (SD) above the mean of the control group. All 39 APS patients had elevated IgG anti-beta 2GPI; however, depletion of IgG from two APS sera diminished, rather than enhanced, binding of IgA. Pre-incubation with purified IgG from a subject with APS led to inhibition of IgA binding at inhibitor levels > 125 micrograms IgG/well. These data demonstrate that patients with APS have IgA anti-beta 2GPI autoantibodies and that the epitope(s) which are recognized by these antibodies can be presented in the absence of cardiolipin or other anionic phospholipids.