The antiphospholipid syndrome (APS) is usually defined by the association of clinical manifestations that comprise venous and/or arterial thrombosis, recurrent fetal losses, and thrombocytopenia, along with the presence of anticardiolipin (aCL) antibodies and/or lupus anticoagulant. Various infectious diseases can induce aCL; however, these antibodies are not usually associated with thrombotic events, as happens with autoimmune diseases, in which these antibodies need the presence of ␤ 2 -glycoprotein I. Levels of immunoglobulin G (IgG) and IgM aCL antibodies were determined by enzyme-linked immunosorbent assay for 243 patients with chronic hepatitis C virus (HCV) infection and 100 healthy controls. Clinical events of APS, the level of ␤ 2 -glycoprotein dependence of aCL, the presence of cryoglobulins and other autoantibodies, and cross-reactivity between purified aCL and HCV were evaluated. Positive results for aCL antibodies were found more frequently (3.3%) for the patients with HCV infection than for healthy controls (0%). All positive aCL antibodies were ␤ 2 -glycoprotein I independent. No significant association was found between aCL antibodies and clinical manifestations of APS, neither was one found between the presence of other autoantibodies or cryoglobulins and that of aCL. Finally, no cross-reactivity between aCL antibodies and HCV antigens was observed. As previously reported, aCL antibodies seem to be an epiphenomenon, and they do not have clinical or laboratory significance in HCV patients.Infection with hepatitis C virus (HCV) may lead to an autoantibody response. It has been reported that chronically infected HCV patients have anti-smooth muscle antibodies, rheumatoid factor, anti-liver-kidney-microsomal (aLKM) antibodies, anticardiolipin (aCL) antibodies, and low titers of antinuclear antibodies (ANA) (1,6,8,31).Antiphospholipid (aPL) antibodies, such as aCL and lupus anticoagulant (LA), are a group of antibodies with an apparent affinity for anionic phospholipids. New data indicate that the antigenic targets of aPL detected in conventional aCL and LA assays are phospholipid-binding plasma proteins, most notably ␤ 2 -glycoprotein I (␤ 2 GPI) and prothrombin, or complexes of these proteins with phospholipids (28). aPL antibodies are detected in patients with autoimmune and infectious diseases and other conditions. In patients with autoimmune diseases, they have been associated with thrombosis, thrombocytopenia, fetal loss, and a variety of other clinical manifestations (livedo reticularis, valvular heart disease, etc.). This clinical association has been defined as antiphospholipid syndrome (APS) (2, 11). In this syndrome, aCL antibodies require ␤ 2 GPI to bind cardiolipin, but aCL antibodies induced by infections do not usually require this cofactor to bind the anionic phospholipid and are considered nonpathogenic (21, 23).In previous studies, members of our group tested aCL antibodies and their cofactor dependence in sera from patients with infectious diseases such as syphilis, leprosy, human ...