Human interstitial or interphotoreceptor retinoid binding protein (IRBP) is a 136,000 molecular weight photoreceptor cell protein capable of inducing an experimental autoimmune uveitis (EAU) in susceptible animal strains. In order to determine specific sites in human IRBP responsible for its uveitopathogenicity, we synthesized 60 peptides, corresponding to its entire 1262 amino acid sequence, and tested each peptide for its ability to induce an EAU in Lewis rats. Three peptides with extensive amino acid sequence homology, designated HIRBP 715, HIRBP 730, and HIRBP 745, were uveitopathogenic when used at a 50 micrograms immunizing dose. The most potent peptide for the induction of EAU was HIRBP 715. Histopathologically a severe inflammatory response was present in the anterior and posterior segments of the eye. In these eyes the retina was infiltrated extensively with inflammatory cells. Focally the photoreceptor cell layer of the retina was destroyed. There was an associated subretinal exudate as well as an occasional subretinal granuloma. The clinical and histopathological changes in the eyes of rats immunized with peptides HIRBP 730 and HIRBP 745 were less severe as compared to HIRBP 715. One additional peptide, HIRBP 720, without extensive amino acid sequence homology to other regions of human IRBP, was also uveitopathogenic under our experimental conditions. Our study identifies multiple uveitopathogenic sites in the human IRBP molecule and, based on the primary amino acid sequence three of these sites are interrelated by several gene duplications which occurred some 600-800 million years ago in the native IRBP molecule.