Complement activation is a relevant driver in the pathomechanisms of vasculitis. The involved proteins in the interaction between endothelia, complement and platelets in these conditions are only partially understood. Thrombospondin-1 (TSP-1), found in platelet α-granules and released from activated endothelial cells, interacts with factor H (FH) and von Willebrand factor (vWF). However, direct regulatory interaction with the complement cascade has not yet been described. We could show that TSP-1 is a potent, FH-independent inhibitor of the alternative complement pathway. TSP-1 binds to complement proteins, inhibits cleavage of C3 and C5 and the formation of the membrane attack complex. Complement-regulatory function is validated in blood samples from patients with primary complement defects. Physiological relevance of TSP-1 is demonstrated in ANCA-associated vasculitis (AAV) patients by significantly enhanced TSP-1 staining in glomerular lesions and increased complement activity and NETosis following TSP-1 deficiency in an in vitro and in vivo model of AAV. The newly described complement-inhibiting function of TSP-1 represents an important mechanism in the interaction of endothelia and complement. In particular, the interplay between released TSP-1 and the complement system locally, especially on surfaces, influences the balance between complement activation and inhibition and may be relevant in various vascular diseases.