The naturally occurring humoral immune response of Campbell and Hunter strains of Royal College of Surgeons (RCS) rat to bovine retinal S-antigen and bovine rod outer segments was tested by a sensitive ELISA (enzyme linked immunosorbent assay) in animals up to the age of 9 weeks. Controls of piebald Virol Glaxo, Wistar and DA rats were also employed. The ELISA results indicate that rats of all strains had a response to both antigens. The magnitude of the response in any particular strain varied with the age of the animal and the antigen and serum dilution employed in the assay, considerable variation in response was observed among animals of the same strain at any one particular age. Immunoblot analysis of the strongest ELISA positive sera detected S-antigen and other autoantigenic proteins in both RCS and Wistar rats. The data suggest that the antibody response observed may have little significance to the retinal degeneration observed with RCS rats.