Genetic regulation of the spontaneous anti-histone antibody production in systemic lupus erythematosus (SLE) was studied using the H-2-congenic and T cell receptorβchain gene complex (TCRβ)-congenic NZB and NZW strains and their crosses. We found that the original, parental H-2d/dNZB mice produced significantly higher titers of serum IgM class anti-histone antibodies than did the congenic H-2d/2or H-2Z/ZNZB mice. However, none of these three NZB strains produced IgG antibodies. The NZW strain of any H-2 haplo-type did not produce IgM and IgG anti-histone antibodies. The IgG anti-histone antibodies were produced only by H-2d/Zheterozygous NZBxNZW Fl, but not by homozygous H-2zft or H-2d'd NZBxNZW Fl mice. In studies using (NZBxNZW) FlxNZB backcross mice, only the progeny having both H-2d/zand NZW-type TCRβgenotypes produced high amounts of IgG antibodies. There was a tight linkage between the NZW-type TCRβand the production of IgG anti-histone antibodies in TCR T-congenic NZBxNZW Fl mice. All these findings were in keeping with our preceding observations on the genetic regulation of anti-DNA antibodies in these mice and suggest that certain common mechanisms such as superantigen-mediated or common idiotope-mediated regulations may underlie the production of these two distinct autoantibodies in NZBxNZW Fl mice.