Experimental autoimmune uveoretinitis (EAU) is a predominantly T-cell-mediated autoimmune inflammatory disease of the retina and uveal tract of the eye. Retinal S-antigen, a protein found in retinal photoreceptor cells, is a potent agent for the induction of EAU in susceptible species and strains. Elevated titers of antibody to S-antigen have been reported in patients with different forms of uveitis. Serum samples from 166 patients and 87 healthy blood donors were tested by immunoblotting against human retinal abstract for IgG, IgM and IgA antibodies to S-antigen. Compared to the controls the patient sera showed a higher incidence of S-specific antibodies (17.5% vs 9.2%). No specific correlation between the presence of any type of uveitis and anti-S antibodies has been found (anterior uveitis 15.1%, posterior 19.6%, panuveitis 18.9%). There was a higher incidence especially with IgG antibodies during active disease (19.7% vs 9.2% in controls). The results suggest that since EAU is T-cell mediated, antibodies in humans may be most important as indicators of autoimmunity rather than mediators of the inflammation. As these anti-S antibodies might be induced by disruption and nonspecific inflammation of the retina and uvea alone, an important and difficult question in patients is whether or not these secondary autoimmune response can contribute to the induction of uveitis.