Comparative mapping between the human and rodent genomes is one approach for positional cloning of complex disease loci. The human type 1 diabetes susceptibility locus IDDM6 has orthology with distal rodent chromosome 18, to which Iddm3 has been mapped in rat. Previously, we mapped Idd21 to mouse chromosome 18. Here, the primary aim was to determine whether Idd21 mapped to distal mouse chromosome 18. We constructed novel congenic strains from the consomic NOD-Chr 18ABH strain and mapped two loci (Idd21.1 and Idd21.2) to the distal 29.3-Mb portion of mouse chromosome 18, orthologous to IDDM6 (human) and Iddm3 (rat). Idd21.3 was mapped to proximal mouse chromosome 18 (0–21.9 Mb). Although Idd21.1 did not influence β-islet inflammation, splenocytes from pre-diabetic Idd21.1-congenic mice were less efficient at transferring diabetes to immunodeficient NOD-scid mice. This suggests that Idd21.1 may act by reducing the pathogenicity of islet-infiltrating immune cells. For the first time, the presence of a non–major histocompatibility complex autoimmune diabetes locus colocalizing in three species has been demonstrated; IDDM6 (human), Iddm3 (rat), and now Idd21.1–21.2 in mouse. Further genetic localization of Idd21.1 and Idd21.2 could expedite characterization of the human IDDM6 region.