A genome scan for B10-derived loci that reduce the frequency of diabetes and insulitis in NOD mice demonstrated a large region (34 cM) of linkage on the proximal end of chromosome 1. This locus was designated Idd5 and encompassed candidate genes including Il1r1, Il1r2, Stat1, Stat4, Nramp1, and Bcl2. In the current study, we have confirmed the existence of Idd5 by developing a series of congenic mouse strains that are resistant to diabetes and determined that Idd5 is actually two genes located within a 9.4-cM interval. Idd5.1 is in the proximal 1.5-cM portion of the interval and contains the candidates Casp8, Cflar (FLIP), Cd28, and Cd152 (CTLA4). Idd5.1 overlaps the orthologous CTLA4/IDDM12 locus in humans. Idd5.2 is in the distal 5.1-cM portion of the 9.4-cM interval and contains the candidates Nramp1, which has a functional polymorphism between NOD and B10, and Cmkar2 (CXCR2, interleukin [IL]-8 receptor alpha). Candidate genes eliminated by this analysis include Il1r1, Ilr2, Zap70, Orch5, Stat1, Stat4, Bcl2, Cmkar4 (CXCR4), and Il10. On its own, the Idd5 locus provides a significant amount of protection from diabetes (50% reduction from parental frequency) and when combined with another resistance locus (Idd3 on chromosome 3), provides nearly complete protection from diabetes and insulitis.