Abstract Type I diabetes (T1D) is an autoimmune disease in which β cells are destroyed by the immune system. Childhood exposure to Group A Streptococci (GAS) is negatively correlated with T1D. Additionally, mice and humans produce N-acetyl-D-glucosamine (GlcNAc) specific antibodies in response to GAS infection. Since GlcNAc-specific antibodies exhibit autoreactivity to β cells, we hypothesized that GlcNAc-specific B cells and their secreted antibodies modulate the development of autoimmune diabetes. When neonatal NOD mice were immunized with GAS or control bacteria and monitored for hyperglycemia and glycosuria, NOD mice immunized with GAS were protected from spontaneous autoimmune diabetes. Moreover, passive transfer of sera from NOD mice immunized with GAS protected WT NOD mice from diabetes, demonstrating a protective role for GlcNAc-specific antibodies in vivo. Purified GlcNAc-specific IgM prevented activation and production of TNFα, IL-2, and IFNγ by diabetogenic T cells in vitro. Finally, immunization with GAS inhibited diabetogenic CD4 T cell activation in pancreatic lymph nodes in vivo. These findings indicate that B cells specific for O-GlcNAc, when activated by microorganism-associated antigens during neonatal development, protect against autoimmune diabetes by a mechanism dependent on secretory autoantibodies. These data identify a potential vaccine-based therapy for T1D in which protective autoantibodies are generated upon exposure to GlcNAc-expressing microorganisms.