Background/Aims: There may be a relationship between autoimmune hepatitis and viral infection, To examine this relationship, 19 patients with autoimmune hepatitis and/or chronic hepatitis C were studied. Methods: Patients were selected initially on the basis of having autoantibodies (anti-nuclear, anti-smooth muscle, or anti-liver-kidney microsomal) in serum. Formalin-fixed, paraffin-embedded liver biopsies from these patients were tested for HCV-RNA by polymerase chain reaction, The biopsies were examined histologically to detect features suggestive of chronic hepatitis C or autoimmune hepatitis, The results were correlated with serum anti-HCV and HCV-RNA, and with response to steroid therapy. Results: Five of the nineteen patients had detectable HCV-RNA in their liver biopsies, In two of three patients from whom serum was available, HCV-RNA was detectable, The remaining 14 patients were negative for HCV-RNA by tissue polymerase chain reaction, Serum was available from 11 of these patients, and serum HCV-RNA was negative in all, All of the three HCV-RNA-positive patients who were treated with steroids showed a partial response; tissue positivity for HCV-RNA was significantly higher in partial responders than in complete responders (60% vs 0%, p=0.01), Severe portal and periportal inflammation with prominent plasma cells together with bridging parenchymal necrosis were seen more often in HCV-negative biopsies, Mild portal and periportal inflammation with portal lymphoid aggregates, apoptosis and spotty parenchymal necrosis were seen more in HCV-positive biopsies. Conclusions: These results show that hepatitis C virus can be detected in some patients with circulating autoantibodies, The ability to detect HCV-RNA in paraffin-embedded archival material provides a valuable addition to the battery of available HCV tests.