Transgenic expression of the MHC (major histocompatibility complex) class II I-Akmolecule was previously shown to effectively reduce the incidence of insulitis in non-obese diabetic (NOD) mice at the age of 20 weeks. We have further characterized the expression and function of the I-Akmolecule and examined its effects on the incidence of diabetes in NOD mice. The newly expressed I-Akmolecule was recognized as an alloantigen by the T lymphocytes of normal NOD mice as shown by mixed lymphocyte reaction (MLR). The levels of endogenous I-Ag7expression on peripheral blood lymphocytes were not affected by the transgene expression. Transgenic NOD mice were completely resistant to spontaneous diabetes, but the treatment by cyclophosphamide, which effectively induces diabetes in normal NOD mice, caused diabetes, although at a much lower incidence than that of normal NOD mice. On the basis of these findings, we discuss the role of I-Akin the prevention of diabetes in NOD mice.