Immunoregulatory gene loci in different organ-specific inflammatory diseases often co-localize. We here studied myelin oligodendrocyte glycoprotein (MOG)-induced EAE in rat strains congenic for arthritis-regulating genome regions on chromosome 4. We used congenic rats with a 70-centimorgan (cM) fragment from the EAE- and arthritis-resistant PVG.1AV1 rat strain on the arthritis- and EAE-permissive Dark Agouti (DA) rat background. In addition, we evaluated three recombinant strains, C4R1-C4R3, which overlap with arthritis-linked loci. PVG.1AV1 alleles in the C4R1 recombinant did not affect arthritis, but conferred protection against MOG-EAE. PVG.1AV1 alleles in the C4R2 recombinant down-regulated arthritis but had no effect in MOG-EAE. Paradoxically, PVG.1AV1 alleles in the C4R3 recombinant down-regulated arthritis, but the same fragment increased serum levels of anti-MOG Ab and aggravated clinical MOG-EAE. Thus, we provide original evidence that the same genome regions can have opposite effects in different organ-specific inflammatory diseases. Interestingly, no apparent difference in the MOG-EAE phenotype was observed in full-length congenic rats and parental DA rats, suggesting that the disease amelioration in C4R1 and aggravation in C4R3 functionally counteract each other. The data set the stage for definition of the mechanisms and positioning of the genes regulating two organ-specific inflammatory diseases differently.