We have previously shown that 1121 mice with 1310 or BALB genetic backgrounds have higher basal levels of IgG2a than H2(k) and H2(d) congenic strains and, hence, have low IgG1/IgG2a ratios, which is consistent with a T1 cytokine milieu. The phenotypic marker of the high IgG2a levels, denoted immunoglobulin isotype-1 (Igis1) was provisionally mapped telomeric of IEbeta using MHC recombinant mice. In addition, data from B10.A(2R), B10.A(1R) and B10.A(18R) mice indicated that Igis1 may lie in a 27 kb region between G7b (Sm-X5) and G7c. In the present study we confirm that Igis1 is in the H2 region using BALB and B 10 congenic F2 mice. H2(bb) F2 mice had higher IgG2a levels than the H2(dd) parental strains. H2(bd) F1 and F2 mice on the B 10 background produced IgG2a levels comparable with the H2(bb) parental strain, indicating that the b allele was dominant. In contrast, the H2bd F1 and F2 mice on the BALB background produced IgG2a levels between those of the H2(bb) and H2(dd) parental strains, indicating codominance of the b and d alleles. This suggests that a background gene influences regulation of IgG2a levels by Igis1. Non-obese diabetic (NOD) mice (K(d)IA(g7)IE(nu11)D(b)), which can develop type I diabetes, had higher levels of IgG2a than NOD-H2(d) congenic mice. Thus, Igis1 affects isotype selection in the presence of non-MHC diabetes genes. As type 1 diabetes is associated with T1 responses, Igis1 may affect susceptibility to this condition.