Studies of mouse lupus models have linked the MHC H2(b) haplotype with the earlier appearance of antinuclear autoantibodies and the worsening of nephritis. However, it is unknown whether H2(b) by itself, in the context of pure nonlupus strains, is "silent" or sufficient with regard to loss of tolerance to chromatin (nucleosomes). In this study we show that, beginning approximately 6-9 mo of age, H2(b)-congenic BALB/c (denoted BALB.B) mice, unlike BALB/c (H2(d)) and H2(k)-congenic BALB/c (denoted BALB.K) mice, develop strikingly increased serum levels of anti-chromatin Ab dominated by the IgG2a subclass, along with minor increase of Abs to DNA and moderately increased total serum IgG2a. The BALB.B mice did not have glomerulonephritis or an increased mortality rate. H2(b)-congenic C3H/He mice (designated C3.SW mice), unlike C3H/He (H2(k)) mice, showed low but measurable serum levels of chromatin-reactive IgG2a Abs and minor but significant hypergammaglobulinemia. By immunofluorescence, IgG2a of sera from both H2(b)-congenic strains stained HEp-2 cell nuclei, confirming the presence of antinuclear autoantibodies. Thus, in the context of two pure nonlupus genomes, the MHC H2(b) haplotype in homozygous form is sufficient to induce loss of tolerance to chromatin.