Pemphigus foliaceus (PF) is an organ-specific autoimmune skin disease characterized by subcorneal epidermal cell detachment (acantholysis) and pathogenic autoantibodies against desmoglein 1. The mechanism responsible for pemphigus autoantibody-induced epidermal injury is not fully understood. In this study, we used the IgG passive transfer mouse model of PF to investigate the relevance of the apoptotic mechanism in pemphigus pathogenesis. TUNEL-positive epidermal cells and increased oligonucleosomes in the epidermal cytosolic fractions were detected in the diseased mice. Time course study reveals that TUNEL-positive epidermal cells appear before intraepidermal blisters. Moreover, the proapoptotic factor Bax was up-regulated at the earlier time points (2 and 4 h), whereas the antiapoptotic factor Bcl-x(L) was down-regulated at the later time points (6, 8, and 20 h) post-PF IgG injection by Western blot analysis. The active forms of caspase-3 and -6 were detected at the later time period (6, 8, and 20 h). Administration of Ac-DEVD-cmk, a peptide-based caspase-3/7 inhibitor, protected mice from developing intraepidermal blisters and clinical disease induced by PF IgG. The same protective effect was also observed using a broad-spectrum caspase inhibitor, Bok-D-fmk. Collectively, these findings show that biochemical events of apoptosis are provoked in the epidermis of mice injected with PF autoantibodies. Caspase activation may contribute to acantholytic blister formation in PF.