The sera of patients with systemic lupus erythematosus (SLE) and drug-induced lupus (DIL) were used to study the antigenic regions of histone 1 (H1) that bind antibodies in these sera. ELISA and immunoblotting techniques using enzymatically and chemically derived peptides of H1 showed that the major antigenic domain is in the carboxyl (C) terminus. None of the 24 SLE or 11 DIL sera bound to the central hydrophobic polypeptide by ELISA. The reactivity of DIL sera with the purified H1 peptides was similar to that observed with SLE sera. This observation suggests a common immune pathway for DIL and SLE.