We described a myopathy in a patient, B.J., with Waldenström's macroglobulinemia and a serum IgM M-protein that binds to a glycoprotein located in skeletal muscle endomysium. The objective of this study was to identify and characterize the endomysial antigen. The antigenic protein was purified using sequential differential solubility steps, size exclusion chromatography, and anion exchange chromatography. We subjected the deglycosylated protein and several proteolytic fragments to sequence analysis. We used immunohistochemistry, Western blot, and ELISA to study the binding of the IgM monoclonal and the anti-decorin core protein antibodies to the muscle antigen before and after deglycosylation. Sequence analysis revealed amino acid residues with 100% homology to human decorin. The anti-decorin core protein antibody bound to the purified antigen by ELISA and Western blot methods and bound to skeletal muscle endomysium in a histologic pattern similar to the human IgM M-protein from the patient B.J. Deglycosylation experiments revealed that the human IgM M-protein from B.J. serum recognized a carbohydrate epitope on decorin, probably containing chondroitin sulfate. A skeletal muscle-specific form of the proteoglycan decorin, with a chondroitin sulfate-like epitope, is a target antigen for the IgM M-protein in our patient with Waldenström's macroglobulinemia and a myopathy. These results are the first demonstration of the binding of a human IgM M-protein to an endomysial antigen. The anti-decorin IgM may be relevant to disease pathogenesis because the patient studied had a myopathy with IgM monoclonal antibodies deposited in the muscle endomysium.