The current paradigm of major histocompatibility complex (MHC) and disease association suggests that efficient binding of autoantigens by disease-associated MHC molecules leads to a T cell–mediated immune response and resultant autoimmune sequelae. The data presented below offer a different model for this association of MHC with autoimmune diabetes. We used several mouse lines expressing different levels of I-A^g7 and I-A^k on the nonobese diabetic (NOD) background to evaluate the role of MHC class II in the previously described NOD T cell autoproliferation. The ratio of I-A^g7 to I-A^k expression correlated with the peripheral T cell autoproliferative phenotype in the mice studied. T cells from the NOD, [NOD × NOD.I-A^null]F1, and NOD I-A^k transgenic mice demonstrated autoproliferative responses (after priming with self-peptides), whereas the NOD.H2^h4 (containing I-A^k) congenic and [NOD × NOD.H2^h4 congenic]F1 mice did not. Analysis of CD4⁺ NOD I-A^k transgenic primed lymph node cells showed that autoreactive CD4⁺ T cells in the NOD I-A^k transgenic mice were restricted exclusively by I-A^g7. Considered in the context of the avidity theory of T cell activation and selection, the reported poor peptide binding capacity of NOD I-A^g7 suggested a new hypothesis to explain the effects of MHC class II expression on the peripheral autoimmune repertoire in NOD mice. This new explanation suggests that the association of MHC with diabetes results from “altered” thymic selection in which high affinity self-reactive (potentially autoreactive) T cells escape negative selection. This model offers an explanation for the requirement of homozygous MHC class II expression in NOD mice (and in humans) in susceptibility to insulin-dependent diabetes mellitus.