Human interstitial retinoid-binding protein (HIRBP) is a 136 kDa retinal protein capable of inducing experimental autoimmune uveoretinitis (EAU) and experimental autoimmune pinealitis (EAP) in Lewis (LEW) rats. In order to identify the T-cell recognition sites of HIRBP responsible for uveitogenic and proliferative responses, 125 overlapping peptides corresponding to its entire 1262 amino acid sequence were synthesized. Individual peptides were tested for their ability to induce EAU in LEW rats and to stimulate lymphocyte proliferation in rats immunized with the native molecule. Our previous results showed the presence of nine uveitogenic peptides in HIRBP with a minimum requirement of eight amino acids needed to induce EAU in LEW rats. Our present studies show nine proliferative peptides, four of which are also responsible for uveitogenicity. Another four peptides known to actively induce EAU were unable to elicit proliferative responses. However, these peptides overlapped or were adjacent to peptides that elicited good proliferative responses. A single, highly proliferative peptide was located on the amino terminus of HIRBP. In addition, EAU was adoptively transferred with lymph node cells (LNC) of LEW rats previously immunized with two synthetic peptides known to be uveitogenic. Our study indicates that human IRBP is a complex molecule containing multiple and spatially distinct T-cell epitopes responsible for its uveitogenicity, adoptive transfer of EAU and proliferative responses.