Experimental autoimmune uveoretinitis (EAU) can be induced in susceptible strains of rats and mice by immunization with purified retinal antigens, and serves as a model for human uveitis. Because strong HLA associations have been noted in a number of human uveitic diseases, we investigated the role of major histocompatibility complex (MHC) vs. non-MHC genes in the control of susceptibility to ocular autoimmunity, using the mouse and the rat EAU models. It was shown that EAU expression in mice requires both a susceptible MHC haplotype and a“permissive”genetic background. MHC control of susceptibility was tentatively mapped to the I-A subregion in H-2k. I-Ekexpression appeared to have an ameliorating effect on disease. Susceptible H-2 haplotypes exhibited highest disease scores on the B10 background, and disease was reduced, or even absent, on some other (nonpermissive) backgrounds. Factors which may determine“permissiveness”or“nonpermissiveness”of a particular genetic background, as studied in mice and rats, may include diverse genetic mechanisms spanning regulation of cytokines, hormones, vascular effects and the T cell repertoire. Taken together, the data suggest that, in individuals susceptible to uveitis by virtue of their MHC, the final expression of disease will be determined by the genetic background.