The specificity of autoantibodies present in the serum of 151 patients with systemic lupus erythematosus (SLE) was investigated by ELISA using as antigen individual histones as well as 17 different core histone synthetic peptides. Many of the sera reacted with four terminal peptides (residues 1-21 and 130-135 of H3, 1-29 of H4 and 1-25 of H2B) while fewer reacted with internal peptides (residues 65-85 of H2A and 40-55 of H3). Of the 151 SLE sera, 88% reacted with one or more of the six core histone peptides whereas only 57% reacted with one or more of the complete core histone molecules. Antibodies to mononucleosomes from chicken erythrocytes were also prepared in rabbits. The rabbit antisera were tested by ELISA using as antigen chromatin subunits, native and denatured DNA, individual histones and 23 natural and synthetic peptides of histones. The antinucleosome antibodies were found to recognize the same peptide fragments as those recognized by the SLE sera.