The aim of this study was to investigate whether hepatitis C virus (HCV) may perturb the immune system towards autoreactivity. We studied the relationship between the prevalence of anti-HCV and the presence of laboratory and/or clinical autoimmune features in 300 patients: lymphoid malignancies (167) and autoimmune disorders (connective tissue diseases 100; idiopathic thrombocytopenic purpura (ITP) 33). As a control, hepatitis B surface antigen (HBV) and anti-hepatitis B core antigen (anti-HBc) were related to the same parameters. Anti-HCV and anti-HBV were detected in 68/300 (22.6%) and 70/300 (24.6%) patients, respectively. HCV prevalence was 18% in lymphoproliferative disorders (anti-HBc 28.1%) and 26% in connective tissue disease (anti-HBc 16.3%). Among ITP cases, 12/33 (36.4%) were anti-HCV+ and 10/33 (30.3%) anti-HBc+. In 24/30 (80%) anti-HCV+ patients with lymphoproliferative disorders at least one serologic or clinical autoimmune abnormality was detected. To the contrary, only 10/45 (22.2%) anti-HBc+ patients with lymphoproliferative disorders had at least one serologic or clinical abnormality (P < 0.0001). A statistically significant correlation was observed between HCV prevalence and the number of autoimmune alterations in both lymphoproliferative and connective tissue disorders, which was not found for anti-HBc. These data suggest that HCV may skew the immune system toward the production of autoantibodies and also support the possibility that some cases of ITP may be linked to both HCV and HBV infection.