Bullous pemphigoid (BP) is a bullous dermatosis associated with autoantibodies directed against the hemidesmosomal Ags BP180 and BP230. Lesional skin is characterized by detachment of the epidermis from the dermis with an intense inflammatory cell infiltrate in the upper dermis. In experimental BP, subepidermal blistering is triggered by rabbit anti-murine BP180 (mBP180) IgG and depends upon complement activation, mast cell degranulation, and neutrophil infiltration. In this study, we determined the role of FcγRs on neutrophils in experimental BP. Mice deficient in FcγRIII (FcγRIII−/−) and those deficient in both FcγRI and FcγRIII (FcγRI&III−/−) but not in FcγRII (FcγRII−/−) were resistant to BP. Pathogenic IgG activated wild-type neutrophils, but not FcγRIII-deficient neutrophils, to secrete proteolytic enzymes. The function of anti-mBP180 IgG depended entirely on its Fc domain; F(ab′)2 of IgG had no pathogenic activities. In wild-type mice injected with pathogenic IgG, an FcγR blocker abolished the BP phenotype and inhibited activation of wild-type neutrophils stimulated by pathogenic IgG. Results from this study establish that FcγRIII plays a critical role in the activation of infiltrating neutrophils and the subsequent blistering in experimental BP.