© 2014 The Society for Investigative Dermatology. Bullous pemphigoid (BP) is an autoimmune skin disease characterized by the binding of autoantibodies to components of the hemidesmosome structure, resulting in an inflammatory response and subepidermal blister formation. To investigate the role of immune orientation in the inflammatory processes associated with disease progression, blister fluid, serum, and biopsy specimens were collected from 31 consecutive BP patients. Blister fluids displayed high levels of IL-6, IL-17, IL-22, and IL-23, whereas transforming growth factor-β was increased in BP sera. However, neither immunocytochemistry on a trans-differentiation model of IL-17-producing peripheral blood mononuclear cells nor immunohistochemistry on BP biopsy specimens could demonstrate the presence of T helper type 17 lymphocytes. Instead, innate immune cells, especially neutrophils, produced IL-17 at the skin lesional site. Of note, superpotent topical corticosteroid application quickly and markedly reduced both IL-17 expression and clinical signs of BP. Consistently, IL-17 upregulated matrix-metalloprotease-9 and neutrophil elastase expression, two proteases involved in blister formation, thereof further demonstrating its role in the progress of BP. Finally, IL-17-induced matrix degradation, originated from neutrophil activation, initiated the formation of an amplification loop of the inflammatory response that could represent the underlying phenomenon leading to the maintenance and even disease extent. Thus, our results could open new therapeutic strategies for BP patients.