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Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of potentially life-threatening autoimmune diseases. The main histological feature in the kidneys of patients with AAV is pauci-immune necrotizing crescentic glomerulonephritis with little immunoglobulin and complement deposition in the glomerular capillary walls. The complement system was not, therefore, initially thought to be associated with the development of AAV. Accumulating evidence from animal models and clinical observations indicate, however, that activation of the complement system — and the alternative pathway in particular — is crucial for the development of AAV, and that the complement activation product C5a has a central role. Stimulation of neutrophils with C5a and ANCA not only results in the neutrophil respiratory burst and degranulation, but also activates the coagulation system and generates thrombin, thus bridging the inflammation and coagulation systems. In this Review, we provide an overview of the clinical, in vivo and in vitro evidence for a role of complement activation in the development of AAV and discuss how targeting the complement system could provide opportunities for therapy.