Abstract Each monoclonal protein (M-protein, or myeloma protein) consists of two heavy polypeptide chains of the same class and subclass and two light polypeptide chains of the same type. Electrophoresis on cellulose acetate membranes is satisfactory for screening, although agarose electrophoresis is more sensitive for detecting small M-proteins. Immunoelectrophoresis should be performed when myeloma, macroglobulinemia, amyloidosis, or a related disorder is suspected. Immunofixation is useful when results of immunoelectrophoresis are equivocal. The recognition of a Bence Jones protein depends on the demonstration of a monoclonal light chain by immunoelectrophoresis or immunofixation of an adequately concentrated urine specimen. The differential diagnosis of an M-protein includes monoclonal gammopathy of undetermined significance (benign monoclonal gammopathy), multiple myeloma, solitary plasmacytoma of bone or extramedullary plasmacytoma, macroglobulinemia, lymphoma, chronic lymphocytic leukemia, and primary systemic amyloidosis.