Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver, frequently associated with thrombocytopenia. As various immune abnormalities have been described in PBC, we hypothesized that thrombocytopenia is also an autoimmune phenomenon in these patients. We therefore assessed the frequency of platelet antibodies and their target platelet glycoprotein (GP) specificities. We investigated 66 PBC patients with a median disease duration of 25 months. Twenty-two patients with alcoholic liver disease and thrombocytopenia served as controls. Specificities of platelet antibodies were determined by the monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay using monoclonal antibodies directed against GPIIb/IIIa and GPIb/IX. The notion that immunoglobulins are nonspecifically bound to platelets was further evaluated by the production of eluates from antibody-coated platelets. The specificities of antibodies in these eluates were again determined by the MAIPA assay. Twenty-six PBC patients had platelet antibodies, whereas antibodies were not detectable in control alcoholic patients. Seven of 13 thrombocytopenic PBC patients had detectable antibodies. Overall, GP Ib/IX and GP IIb/IIIa served in a similar frequency as target antigens. Antibody specificities were confirmed by the production of eluates from platelets. These studies provide evidence that antibodies are specifically bound to platelets in patients with PBC and that the development of immune phenomena in PBC may also involve immuno-mediated platelet destruction.