BACKGROUND Serum autoantibodies such as antinuclear antibody (ANA) are frequently detected in patients with chronic hepatitis C virus (HCV) infection, but its relevance is a matter of discussion. OBJECTIVE To assess the association of ANA positivity with clinical and histological features, and with the outcome of antiviral therapy in patients with HCV infection. METHODS Baseline samples from patients with hepatitis C treated with interferon and ribavirin were tested for ANA positivity by indirect immunofluorescence. RESULTS The mean age was 48.3+/-11.1 years and 56% were men. Among 234 included patients, 22 patients (9.4%) were positive for ANA. These patients showed significantly higher median alanine aminotransferase level (3.52 vs. 2.39 x upper limit of normal, P=0.009) when compared with ANA-negative patients. Fibrosis stage and necroinflammatory grading were not influenced by ANA positivity. Sustained virological response (SVR) rates were similar between ANA-positive and ANA-negative patients (27 vs. 29%, P=0.882). Alanine aminotransferase flares (> or = 1.5-fold the baseline) during treatment were observed in 28 patients (12%), irrespective of the presence of ANA and without any clinical significance. CONCLUSIONS Among HCV patients, ANA positivity seems to represent an immunological epiphenomenon. It neither influences clinical, biochemical, and histological features of chronic hepatitis C nor predicts response to antiviral treatment.