Mucous membrane pemphigoid or cicatricial pemphigoid is a mucocutaneous blistering disease characterized by autoantibodies to different molecules in the basement membrane zone. Our objectives were to identify the target antigen recognized by sera from 20 untreated patients with pemphigoid disease limited to the oral cavity, and to determine the pathogenicity of autoantibodies in oral pemphigoid, with an organ culture model. We conducted indirect immunofluorescence, immunoblot, and immunoprecipitation assays, with accompanying absorption experiments, using normal human skin, conjunctiva and gingiva, bovine gingiva and a tumor cell line, which were reacted with sera from patients with oral pemphigoid, anti-alpha6 antibody, and control sera. Sera of oral pemphigoid patients selectively and specifically bound to human alpha6 integrin, a 120-kDa protein present in gingiva and the tumor cell line. Oral pemphigoid sera and anti-alpha6 antibody produced separation of epithelium from basement membrane (blister formation) of normal human buccal mucosa, after 48 hours, in organ culture.