The complement system plays an important role in the activation of the inflammatory response to injury, although inappropriate complement activation (CA) can lead to severe tissue damage. Maggot therapy is successfully used to treat infected wounds. In this study, we hypothesized that maggot excretions/secretions influence CA in order to modulate the host's inflammatory response. Therefore, the effect of maggot excretions on CA was investigated in preoperatively and postoperatively obtained sera from patients. Our results show that maggot excretions reduce CA in healthy and postoperatively immune-activated human sera up to 99.9%, via all pathways. Maggot excretions do not specifically initiate or inhibit CA, but break down complement proteins C3 and C4 in a cation-independent manner and this effect proves to be temperature tolerant. This study indicates a CA-reducing substrate that is already successfully used in clinical practice and may explain part of the improved wound healing caused by maggot therapy. Furthermore, the complement activation-reducing substance present in maggot excretions could provide a novel treatment modality for several diseases, resulting from an (over)active complement system.