NOD mice spontaneously develop anti-insulin autoantibodies associated with the subsequent development of diabetes. NOD mice that express insulin autoantibodies at 8 weeks of age have a diabetes risk exceeding 90%, while mice that do not express autoantibodies by 16 weeks have a risk of less than 20%. NOD female mice expressed insulin autoantibodies more often than male mice (13/15⁺vs. 6/15⁺). Autoantibodies characteristically developed between 8 and 20 weeks and then for most mice became negative at diabetes onset in NOD mice. In the diabetes-free strain NOR mice, spontaneous expression of insulin autoantibodies was observed in less mice (female 8/15⁺, male 3/10⁺) compared to NOD mice. The expression of autoantibodies was transient in NOR mice and followed the same time-course as for NOD mice and they were all negative by 28 weeks (without progression to diabetes). No correlation was found in NOR mice between the levels of autoantibodies and insulitis. The program of insulin autoantibody expression is regulated over approximately 5 months for both NOD and NOR mice with only NOD mice developing diabetes, indicating that depending upon genetic combination, the presence of insulin autoantibodies does not always predict diabetes development. In addition, this data is not consistent with the hypothesis that the time-course of autoantibodies simply reflects the destruction of β-cells with development of diabetes.