Pemphigus vulgaris (PV) is a dermatosis mediated by autoantibodies against desmoglein 3 (Dsg3). It was known that intraperitoneal (i.p.) injections of PV IgG and PV F(ab')2, but not of PV Fab, into neonatal mice reproduced the key features of the disease in these animals. It was proposed that crosslinking of antigen by bivalent PV autoantibodies may trigger acantholysis in PV. In the present study, we have used subcutaneous (s.c.) injections of PV IgG and its proteolytic fragments into neonatal mice to test equimolar amounts of these autoantibody fractions. Mice developed clinical and histological features of PV in a dose-dependent manner following a similar time course. PV IgG and Fab fractions induced acantholysis as early as 2 hr after the injection. It was also demonstrated that sc injections of PV Fab were more effective in inducing disease than ip injections. PV autoantibodies may bind an "adhesive site" of Dsg3 and impair its function, thus triggering acantholysis.