Autoantibodies in the serum of patients suffering the blistering skin disease pemphigus vulgaris recognize a 140-kDa glycoprotein (GP) present in enriched fractions of bovine tongue epidermal desmosomes. Immunofluorescence observations of cryostat sections of bovine tongue epidermis reveal that affinity-purified rabbit antibodies to the 140-kDa GP generate a punctate intercellular stain that is similar to that generated by antibodies directed against a desmosome plaque component (desmoplakin). In cultured mouse keratinocytes, the antibodies against 140-kDa GP recognize desmosomes along areas of cell-cell contact. Double immunofluorescence of cultured keratinocytes with these antibodies and a desmoplakin antiserum reveals that the antibodies against the 140-kDa GP stain a single fluorescent line along areas of cell-cell contact. This single fluorescent line lies between double fluorescent lines generated by the desmoplakin antiserum. Immunogold ultrastructural localization reveals that the 140-kDa antigen is localized not only along the intercellular area of the desmosome but also is found along the whole epidermal cell surface. The antibodies to the 140-kDa GP are able to induce a disruption of cell-cell contact in cultured keratinocytes that possess desmosomes. We propose that the 140-kDa GP is a cell adhesion molecule (CAM). Furthermore we discuss the heterogeneity of desmosomes in the light of our findings that antibodies against the 140-kDa GP recognize specific stratified squamous epithelial tissues.