Epiplakin, a cytoskeletal linker protein, was originally identified as an autoantigen in a serum specimen obtained from a patient with subepidermal blistering disease. To examine the binding ability of epiplakin with intermediate filaments (IF), we performed slot-blot assays using fusion proteins that included various domains and subdomains of epiplakin. At least two of the 4.6 copies in the B domains of epiplakin were necessary for the binding of fusion proteins to keratin. The repeated structures of linker domains also played an important role in the binding of epiplakin to keratin in these assays while also increasing the repeated structure in the linker domain of epiplakin which is involved in the increased binding to IF. A similar but weaker binding to vimentin and desmin was also detected. These observations indicated that the highly repeated structures of epiplakin in both the B and the linker domains, which is the unique feature of this molecule in the plakin family, play an essential role in the functioning of this molecule.