Recently, it has been shown that desmoglein, pemphigus foliaceus target antigen, and a 130-kD pemphigus vulgaris antigen belong to the cadherin family of cell adhesion molecules. We tried to determine whether desmocollins I/II, other cadherin-like transmembranous glycoproteins present in desmosomes, are also recognized by pemphigus autoantibodies of the IgG class. We examined 16 pemphigus vulgaris sera, 15 pemphigus foliaceus sera, 15 Brazilian pemphigus foliaceus sera, five bullous pemphigoid sera, and 65 normal sera. Four (25%) pemphigus vulgaris sera, one (7%) pemphigus foliaceus serum, eight (53%) Brazilian pemphigus foliaceus sera, and three (5%) normal sera reacted with desmocollins I/II on immunoblots of bovine desmosome preparation. The affinity-purified desmocollins I/II pemphigus autoantibodies were shown to bind the epidermal cell surface by indirect immunofluorescence. Immunoblot analysis revealed one pemphigus vulgaris serum, one Brazilian pemphigus foliaceus serum, and one normal serum recognizing a recombinant protein produced by a desmocollin cDNA clone. Moreover, immunoblot analysis of reactivity of a Brazilian pemphigus foliaceus serum with recombinant proteins produced by deletion mutants of the desmocollin cDNA clone showed that the extracellular portion of desmocollin is immunogenic in this pemphigus patient. We conclude that desmocollins I/II are recognized by certain sera from patients with various types of pemphigus, particularly Brazilian pemphigus foliaceus. However, the significance of this reactivity remains to be defined.