The BB rat spontaneously develops insulin-dependent diabetes mellitus (IDDM) as an autoimmune abnormality involving the class II molecules of the major histocompatibility complex (MHC). The rat MHC (RT1 complex) encodes two class II loci, RT1 .B and RT1.D. The possibility that variant or unique class II MHC molecules may be associated with IDDM susceptibility was directly examined by determining the nucleotide sequences of class II mRNAs and/or cDNAs from the diabetes-prone (DP) BB rat, the diabetes-resistant (DR) BB rat, the normal histocompatible Wistar-Furth (WF) rat, and the Lewis rat. Sequence analysis indicates that the β-chains of the RT1.B and RT1.D molecules of the u haplotype from DP-BB, DR-BB, and WF rats are identical but that they are different fromother rat alleles and published mouse class II sequences. At the nucleotide level, the NH2-terminal domain of RTI.Dp of the BB and WF rats differs by a single silent nucleotide substitution. Comparisons with the sequences of the Lewis rat indicate hypervariable allelic differences and that the u and / haplotypes are remarkably similar. These findings establish that the class II molecules of the DP-BB rat are not variant or unique and that unaltered class II molecules of the u haplotype support the autoimmune response in the BB rat.