Preimmunization of Lewis rats with anti-S antigen (S-Ag) monoclonal antibodies (mAb) led to protection against experimental autoimmune uveoretinitis (EAU) induced by this retinal autoantigen. High titers of anti-idiotypic (anti-Id) antibodies were raised against three mouse mAb, S2D2 (IgG2b), S6H8 (IgG2a) and S7D6 (IgG1), directed at S-Ag. An almost complete prevention was observed in S2D2 mAb-immunized animals while a partial protection was achieved with S6H8 and S7D6 mAb. No detectable anti-Id antibody nor disease prevention was observed in rats immunized with the mAb S9E2 (IgG2a) which only recognizes bovine and sheep S-Ag, or with control mAb of the same isotypes irrelevant to S-Ag. The mAb treatment did not modify the level of the whole polyclonal antibody response to S-Ag. These results suggest an important role in the pathogenesis of EAU for the epitopes recognized by S2D2-S6H8 and S7D6 in the S-Ag molecule. The success of anti-Id immunization for autoimmune disease suppression may depend on the identification of relevant epitopes.