INSULIN-dependent diabetes mellitus is characterized by the infiltration of lymphocytes into the islets of Langerhans of the pancreas (insulitis) followed by destruction of insulin-secreting β-cells leading to overt diabetes^1–5. The best model for the disease is the non-obese diabetic (NOD) mouse^6,7. Two unusual features of the class II major histocompatibility complex (MHC)^8,9 of the NOD mouse are the absence of I-E⁹ and the presence of unique I-A molecules (I-A^NOD)¹⁰, in which aspartic acid at position 57 of the β-chain is replaced by serine. This feature is also found in the HLA-DQ chain of many Caucasians with insulin-dependent diabetes mellitus^11–13. We have previously reported that the expression of I-E prevents the development of insulitis in NOD mouse^14,15. Here we report that the expression of I-A^k (Aα^kAβ^k) in transgenic NOD mice can also prevent insulitis, and that this protection is seen not only when the I-A β-chain has aspartic acid as residue 57, but also when this residue is serine. These results show that the single amino-acid substitution at position 57 of the I-A β-chain from aspartic acid to serine is not sufficient for the development of the disease.