Background: In this study, we determined whether low-titre auto-antibodies are a risk factor for the development of autoimmune disease during interferon-alpha (IFN alpha) therapy for chronic hepatitis C (CHC) infection. Methods: Eighty-three patients with circulating hepatitis C virus RNA and chronic viral hepatitis on liver biopsy, who had not received IFN alpha, were assessed for serum auto-antibodies (anti-nuclear antibodies (ANA), anti-smooth muscle antibodies, thyroid microsomal antibodies, thyroglobulin antibodies) and thyroid function tests. Results: Thirty-five patients had one or more pre-existing auto-antibody. The majority were low titre ANA. Seven of the 35 patients had clinical autoimmune disease or immune-mediated disorders, predominantly thyroid disease. Twenty patients with low titre auto-antibodies received treatment with IFN alpha and of these 20 patients, six patients developed adverse effects with a possible auto-immune basis. In comparison, only five of the 48 patients without auto-antibodies had immune-mediated disorders and no patient developed autoimmune complications during therapy with IFN alpha. Conclusions: These results suggest that the presence of low-titre auto-antibodies may be a risk factor for the development of autoimmune dysfunction during IFN alpha therapy for chronic hepatitis C. Patients with no detectable auto-antibodies have a low risk for developing autoimmune complications during treatment with IFN alpha. (C) 1999 Blackwell Science Asia Pty Ltd.