To investigate the specificity, sensitivity, and concomitant presence of antibodies against histones (H), histone H1 (H1), and histone H3 (H3) in patients with systemic lupus erythematosus (SLE) and analyze their association with SLE. Serum IgG anti-histones antibodies were detected by enzyme-linked immunosorbent assay in 144 SLE patients consisting of 24 neuropsychiatric lupus (NPSLE), 65 lupus nephritis (LN), and 55 SLE, 100 other rheumatic diseases patients, as well as 40 healthy controls. Clinical and biological parameters of the patients were also evaluated. Anti-H, anti-H1, and anti-H3 antibodies yielded a sensitivity of approximately 33% and a specificity of more than 93% for SLE, which was comparable to that found for anti-double-stranded DNA (anti-dsDNa) antibodies. More significantly, anti-histone antibody is found in approximately 50% of patients with NPSLE compared with LN. Moreover, the titers of anti-histones antibodies of NPSLE patients were significantly higher than that of patients with SLE and LN. The sequential analysis revealed a close correlation of anti-H and anti-H1 antibodies with SLE disease activity. There was an approximate 30% positive rate of anti-histones antibodies in 144 SLE patients lacking anti-nucleosome, anti-mDNA, anti-Sm, and anti-dsDNA antibodies. Antibodies to histones H1 and H3 are markers with high specificity of 93.6-96.4% for SLE. The anti-histone antibody markers are prevalent in approximately 50% of NPSLE. Furthermore, there was a strong correlation with SLE disease activity index and levels of antibodies to histones and H1.