By several crossing studies it has been demonstrated that the MHC class-II genes of the RT1u haplotype, Iddm1, and the lymphopenia, Iddm2, are essential, but not sufficient for diabetes development in the BB rat. Using diabetic BB/OK and diabetes-resistant DA rats it has been shown that a third non-MHC gene, Iddm3, on chromosome 18 cosegregates with diabetes in the BB/OK rat subline. Because mapping results need not be consistent among different crosses, we genetically analysed a new cross population using diabetic BB/OK and diabetes-resistant SHR/Mol rats analysing 73 microsatellite markers. The genetic analysis of Iddm1 and Iddm2 homozygous [(BB/OK x SHR)F1 x BB/OK] first backcross hybrids (BC1) confirmed the action of Iddm3 and one predisposing non-MHC locus, Iddm4, near Ighe/D6Mgh2 on chromosome 6 and one protective locus, Iddm5r(esistance), detected around Igf2/Tnt on chromosome 1. From these novel findings it is concluded that the diabetogenic phenotype of the BB/OK rat subline is the result of the interaction of predisposing and protecting diabetes genes.