To identify the immunogenic and immunopathogenic sites present in human S-Antigen (S-Ag), 40 overlapping peptides that span the whole length of the S-Ag molecule were synthesized and tested in the Lewis rat model of experimental autoimmune uveitis. The most pathogenic sequences were 180-200, 340-360 and 350-370. Ten peptide sequences were identified that induced visible inflammation in the eye. A total of 23 peptides gave an in-vitro proliferative response following immunization in animals. The ability to generate an immune response was not linked to the pathogenic capacity of the sequence. The most pathogenic sequence, 340-360, was only weakly proliferative. Peptide 180-200 and peptide 340-360 gave higher T-cell proliferative responses, but these were lower than the maximal proliferative response observed with non-pathogenic sequences. In animals immunized with whole S-Ag, the majority of the determinants did not elicit a proliferative response, indicating that in S-Ag, the majority of the immunogenic determinants are cryptic and are not presented by the APC located in the lymph nodes.