In order to assess the serological profile in relation to other serological and histological markers of hepatitis delta virus (HDV) infection we have investigated the presence of autoantibodies during acute and chronic delta infection in 353 serum samples from different patients with acute and chronic hepatitis and autoimmune diseases. Basal cell layer antibodies (BCLA) were found in 58% acute hepatitis B, in 73% chronic hepatitis D and in 4% primary biliary cirrhosis. Stellate thymic epithelial cell antibodies (SECA) were detected in 40% acute D hepatitis and in 49% chronic D hepatitis. No tissue autoantibodies were detected in 50 acute B hepatitis, 35 autoimmune chronic liver diseases, 24 connective tissue diseases or 25 controls. In addition, two previously unreported specificities of anti-thymic antibodies reacting with reticular (TRA) and perithymocytic cells (PTA) were identified in 33% and 9% acute D hepatitis, respectively, and in 13% and 6% chronic D hepatitis cases. Among patients with acute HBV-HDV coinfection these antibodies were detected transiently (less than 4 weeks) and at low titer, whereas in those with chronic infection autoantibodies levels tend to be high and persistent throughout the follow-up. Among patients with chronic HDV infection no correlation was found between the presence of tissue autoantibodies and hepatic delta antigen expression and serum HDV-RNA which suggest that autoimmune phenomena observed during chronic delta infection are not related to the level of viral replication.