Lymphocytotoxic activity of sera from systemic lupus erythematosus (SLE) patients and their families was inhibited by 50% or more by preincubation of target cells with Fab2 fragments of xenoantisera against beta 2 microglobulin or the heavy chain of the HLA-A,B,C antigenic molecular complex. An antiHLA-DR xenoantiserum had less blocking effect on peripheral blood mononuclear cells but was effective at blocking reactivity of these sera against cultured B lymphoid cell lines. The repertoire of specificities in family members' sera differed from each other and their respective proband with respect to their reactions with cultured lymphoid cell lines. These data indicate that lymphocytotoxic antibodies (LCA) found in most patients with SLE and some of their relatives include a subpopulation with specificity for determinants present on major histocompatibility gene products. They also suggest that LCA in relatives represent a defect in immune regulation which allows expression of existing autoimmune potentials rather than immunization with a single "lupus" antigen.