Retinal interphotoreceptor retinoid-binding protein (IRBP) is a potent uveitogen in Lewis rats, producing experimental autoimmune uveitis (EAU) reproducibly at doses lower than those of S-antigen (S-Ag). In contrast, IRBP was found to be poorly uveitogenic in three strains of guinea pigs, inducing only minor changes in a small proportion of these animals. On the other hand, S-Ag was found to induce EAU in the majority of immunized guinea pigs, with changes more severe than those induced by IRBP. Unlike the difference in their uveitogenicity, IRBP and S-Ag induced similar levels of specific immune responses in the immunized guinea pigs. The poor uveitogenicity of IRBP in guinea pigs resembles that of A-antigen (A-Ag). The two proteins are also similar in other features and were found in this study to be antigenically identical. It is proposed that IRBP and A-Ag are one and the same protein.