The immune response to self antigens is regulated through an interplay of idiotypes and anti-idiotypes expressed on antibodies and lymphoid cells. The equilibrium of the different components of the immune system has been modulated in various autoimmune diseases by manipulation of the idiotypic network. Experimental autoimmune uveoretinitis (EAU) was induced in rats with one foot pad injection of S-antigen (S-Ag) in complete Freund's adjuvant (CFA). 1. Injection of rats with the mouse anti-S-Ag monoclonal antibody (mAb) S2D2 either simultaneously with or before S-Ag challenge, led to an anti-idiotypic (anti-Id) response and to inhibition of EAU. 2. Suppression of the disease could be passively transferred using lymph node and/or spleen cells from donors immunized with S2D2 to naive recipients, prior to immunization with bovine S-Ag in CFA. In contrast, one injection of IgG from S2D2-immunized rats did not prevent EAU. 3. Preimmunization against a purified rat polyclonal anti-Id-S2D2 antibody (internal image of the epitope recognized by mAb S2D2) before S-Ag challenge also allowed to inhibit EAU. As S2D2 was the best of several anti-S-Ag mAbs tested for disease inhibition, the epitope recognized by S2D2 should be of particular interest in the regulation of the immune response. This epitope has been localized to the N-terminal region of S-Ag, in the amino acid sequence 40–50. The S2D2 epitope is distant from all presently known uveitogenic sites. Manipulation of the idiotypic network for selected epitopes of the autoantigen may provide a valuable approach to therapy of autoimmune disease.