B ullous pemphigoid (BP) is an autoimmune disease characterized by subepidermal vesicles and the presence of autoantibodies directed against the epidermal basement membrane zone. Previous studies have identified two protein components of the hemidesmosome, BP180 and BP230, as the primary antigenic targets of BP autoantibodies. We have recently reported the isolation of a 1.0-kb BP180 cDNA. Sequence analysis presented in this report reveals that this partial BP180 cDNA encodes two protein domains which have primary structures that are characteristic of the triple helical domains of collagens, i.e., glycine appears at every third position and over one-third of the remaining residues are proline. The two collagen domains have lengths of 242 and 30 amino acids and are separated by a noncollagen stretch of 12 amino acids. Collagenase digestion of the BP180 cDNA-encoded fusion protein generated a peptide fragment with a size that was consistent with the predicted locations of the collagenase digestion sites. A possible physiological function for the collagen domains of the BP180 hemidesmosomal protein may be to form stable interactions with constituents of the extracellular matrix of the cutaneous basement membrane zone. Such interactions may provide the molecular framework for the adhesion between the basal keratinocyte and the basal lamina.