Bullous pemphigoid (BP) is an autoimmune skin disease that is characterized by the presence of subepidermal blisters resulting from a disruption of the adhesive interactions between basal keratinocytes and the cutaneous basement membrane. Autoantibodies from patients suffering from this disorder recognize two epidermal antigens, BP180 and BP230, both of which have been localized to the hemidesmosome, a transmembrane structure of stratified, squamous epithelia that functions in cell-matrix adhesion. In the present study we report the primary structural analysis of BP180 based on the sequence of a series of overlapping cDNA clones encompassing 4,669 bases of the BP180 transcript. A polymerase chain reaction-based protocol was used to confirm the contiguity of the cDNA segments. This cloned portion of the BP180 transcript was found to contain one long open reading frame (ORF) 4.596 bases in length. This ORF encodes a polypeptide of 155,000 Daltons with an isoelectric point of 9.7. The carboxy-terminal half of BP180, a stretch of 916 amino acids, consists of 15 collagen domains of variable length (15 to 242 amino acids) that are separated from one another by short stretches of non-collagen sequences. Located 76 amino acids upstream of the collagenous region is a putative transmembrane domain, a structural feature that distinguishes BP180 from all of the well-characterized members of the collagen family. This membrane-spanning domain is predicted to function as a signal-anchor sequence, directing the C-terminal collagenous segment of this protein to the exterior of the cell. The putative intracellular domain is highly basic with an isoelectric point of 10.37. This molecular analysis predicts that the BP180 antigen is an integral membrane protein of the hemidesmosome that contains a long extracellular collagenous tail. This combination of structural features suggests that BP180 may function as a cell-matrix adhesion molecule, with the collagenous region acting as a potential site of interaction with basement membrane components. Autoantibody-mediated disruption of such an adhesive interaction may play a critical role in the development of sub-epidermal blisters in BP patients.