Pemphigus vulgaris antigen (PVA) is a member of the desmoglein subfamily of the cadherin supergene family. PVA has homology to the classical cadherins (e.g., E-cadherin), both in its extracellular and cytoplasmic domains. Classical cadherins possess certain well-defined and characteristic biochemical properties of both domains. The cytoplasmic domain binds α-,β-, and γ-catenins. The extracellular domain is protected by calcium from degradation by trypsin. In this study we show that PVA does not share these characteristic biochemical features. Immunoprecipitation of E-cadherin and PVA from human keratinocytes shows that under the same conditions in which the catenins co-precipitate with E-cadherin, only plakoglobin (which co-migrates with γ-catenin) co-precipitates with PVA. Treatment of keratinocytes with 0.01% trypsin in 1 mM calcium (T/C) does not degrade the extracellular region of E-cadherin, but does partially degrade that of PVA. This increased T/C susceptibility of PVA is not due to its cytoplasmic domain, as the same sensitivity of the extracellular domain of PVA to T/C was observed in L cell clones transfected with a chimeric cDNA that encoded for the extracellular domain of PVA and the cytoplasmic domain of E-cadherin. These data demonstrate that although the desmogleins and classical cadherins share striking amino acid homologies in both the cytoplasmic and extracellular domains, they do not exhibit identical biochemical properties and, by extension, may not subserve identical cell biologic functions.