Anti-SLA antibodies characterize a newly defined subgroup of patients with autoimmune chronic active hepatitis. The aim of the present study was the immunochemical characterization of the target antigen(s) of anti-SLA antibodies. Anti-SLA-positive sera were found to contain high titres of anti-cytokeratin antibodies. In immunoblotting analyses with 100,000 x g supernatants of human liver homogenates (S-100) these sera recognized various proteins with a molecular mass of 40-60 kDa. These proteins were also recognized by monoclonal anti-cytokeratin antibodies. Two-dimensional co-electrophoresis and immunoblotting analysis of S-100 and liver cytokeratins showed that anti-SLA antibodies were primarily directed against cytokeratins, particularly against liver cytokeratin types 8 and 18. This was supported by affinity chromatography, immunofluorescence and absorption methods using anti-SLA sera.