Bullous pemphigoid (BP) is an autoimmune skin-blistering disease characterized by the presence of autoantibodies against the hemidesmosomal proteins BP230 and BP180. In the IgG passive transfer mouse model of BP, subepidermal blistering is triggered by anti-BP180 antibodies and depends on the complement system, mast cell (MC) degranulation, and neutrophil infiltration. In this study, we have identified the signaling events that connect the activation of the complement system and MC degranulation. We found that mice deficient in MCs or the C5a receptor (C5aR) injected with pathogenic anti-BP180 IgG failed to develop subepidermal blisters and exhibited a drastic reduction in p38 MAPK phosphorylation compared with WT mice. Local reconstitution with MCs from WT but not C5aR-deficient mice restored high levels of p38 MAPK phosphorylation and subepidermal blistering in MC-deficient mice. Local injection of recombinant C5a induced phosphorylation of p38 MAPK in WT but not MC-deficient mice. Cultured mouse MCs treated with recombinant C5a exhibited a significant increase in p38 MAPK phosphorylation and MC degranulation. Taken together, these data demonstrate that C5a interacts with C5aR on MCs and that this C5a-C5aR interaction triggers activation of the p38 MAPK pathway, subsequent MC degranulation, and ultimately BP blistering.