Pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are autoimmune blistering diseases characterized by autoantibodies against desmoglein (Dsg)1 and Dsg3, respectively. The role of classical cadherins as immunological targets of pemphigus autoantibodies is unknown. In this study, we tested the reactivity of sera from patients with PF, Fogo Selvagem (FS), and PV by immunoprecipitation coupled with immunoblotting (IP-IB) and ELISA techniques using a baculovirus-expressed ectodomain of E-cadherin. By IP-IB, anti-E-cadherin reactivity was detected in all tested sera of PF (n=13) and FS (n=15) patients, and in 79% of mucocutaneous-type PV patients (n=33), but in none of the mucosal-type PV patients (n=7). By ELISA, anti-E-cadherin IgG was detected in most pemphigus sera that produced strong E-cadherin bands by IP-IB. The immunoreactivity of PF/FS sera with E-cadherin was also demonstrated by IP-IB using human epidermal extracts. However, immunofluorescence staining of A431DE cells (E-cadherin positive, Dsg1 negative) with pemphigus sera showed negative results. Immunoadsorption and competitive ELISA analysis suggest that most of the anti-E-cadherin antibodies cross-react with Dsg1, whereas others may represent independent antibodies that do not cross-react with Dsg1. The functional relevance of these anti-E-cadherin IgG autoantibodies detected in these pemphigus sera remains to be defined. © 2008 The Society for Investigative Dermatology.