The mapping of B-cell epitopes on antigen molecules is best done with monoclonal antibodies (MAbs). Most methods require physical chemical procedures for purifying, binding, or labeling the antigen or the MAb. These procedures require some technical proficiency, may present methodological problems, and are based on much trial and error, but, worst of all, these manipulations, including the simple adsorption of molecules to surfaces, may induce the unfolding of the protein antigen, and therefore the loss of native epitopes with the exposure of new determinants (“unfoldons”) (1 ). Thus, when a mapping technique is successfully set up, there is often the nagging question: “Is the antigen still in its native conformation?” Our immunodiffusion method avoids many of these problems since in most instances, both the antigen and the antibody can be used without any manipulation. The method is based on the fact that a single MAb generates soluble immune complexes with an antigen, but two MAbs to different epitopes, when tested in appropriate conditions, generate insoluble complexes that are detected as a precipitin line.