Circulating immune complexes have been implicated in the development of tissue injury in many chronic disease states, but in most instances the inciting antigens have not been identified. This report describes the development of a sensitive enzyme-linked immunosorbent assay which can be used to screen rapidly and simultaneously the immune complexes of numerous sera for the presence of a suspected antigen. The prototype antigen sought here was kappa-casein, a frequent participant in immune complex formation in IgA deficiency and in atopic diseases. The enzyme-antibody conjugate described here can detect as little as 0.11 ng/ml of kappa-casein; for immune complexes formed in vivo or in vitro, one can distinguish circulating complexes containing casein from complexes not containing this antigen. Using this reagent, a major antigen in the immune complexes of hypogamma-globulinemic patients treated with intravenous gamma-globulin was unexpectedly identified as kappa-casein. This method of specific immune complex analysis is suggested as a practical and effective approach to the elucidation of the antigenic constituents of immune complexes found in many diseases.