An immunodominant and potentially pathogenic epitope associated with bullous pemphigoid (BP) and herpes gestationis (HG) has recently been mapped by our laboratory to a noncollagenous stretch of the extracellular domain of the human BP180 antigen. This antigenic site, designated the MCW-1 epitope, has been shown to be recognized by the majority of BP and HG sera. Interestingly, the MCW-1 epitope is absent from the murine BP180 molecule, and therefore, human autoantibodies directed against this site could not be tested for pathogenicity using the conventional passive transfer mouse model. Alternatively, rabbit antibodies were prepared against recombinant forms of the human MCW-1 epitope and the murine NC16A domain and were tested for pathogenicity by passive transfer experiments. Neonatal mice injected with rabbit antimurine BP180 IgG developed a subepidermal blistering disease that closely mimicked BP and HG at the clinical, histological and immunological levels. Rabbit IgG specific for the human MCW-1 epitope was not pathogenic. These results suggest that the autoantibodies against the MCW-1 epitope of the human BP180 antigen found in BP and HG sera may be relevant in the pathogenesis of blister formation in these patients.