In an earlier study we isolated three cyanogen bromide cleavage fragments of bovine IRBP that exhibited high levels of immunopathogenicity, producing inflammatory changes in the eyes (EAU) and pineal gland (EAP) of Lewis rats. These fragments have been localized within the IRBP sequence. In order to identify these putative immunopathogenic epitopes of IRBP, nine selected peptide sequences were synthesized and tested for the induction of disease in Lewis rats. Seven of the peptides were found inactive in producing disease while two closely related peptides, designated R4 (23-mer) and R9 (27-mer) were found to reproducibly induce EAU and EAP in immunized rats. No good correlation was found between the immunopathogenicity of the nine tested peptides and their amphipathicity: peptides R4 and R9 were not predicted to form strong amphipathic helices, while peptides selected for their high predicted helical amphipathicity were not immunopathogenic. EAU induced by peptides R4 and R9 was less severe and had a longer onset time than the disease induced by whole IRBP. In addition, the inflammatory changes induced by R4 and R9 in the posterior segment of the eye were less acute than those induced by whole IRBP and included granuloma formation and perivasculitis, features which are not generally seen in rats immunized with whole IRBP. Thus, the changes induced by R4 and R9 more closely resemble those which are characteristically found in human eyes affected by certain uveitic diseases than do changes produced by the intact protein.