Infestation of skin by the parasitic itch mite Sarcoptes scabiei afflicts 300 million people worldwide, and there is a need for novel and efficient therapies. We have identified a multigene family of serine proteases comprising multiple catalytically inactive members (Scabies Mite Inactivated Protease Paralogues—SMIPP-Ss), which are secreted into the gut of S. scabiei. SMIPPs are located in the mite gut and in feces excreted into the upper epidermis. Scabies mites feed on epidermal protein, including host plasma; consequently, they are exposed to host defense mechanisms both internally and externally. Two recombinantly expressed SMIPP-Ss inhibited all three pathways of the human complement system due to binding of C1q, mannose-binding lectin, and properdin. Immunohistochemical staining demonstrated the presence of C1q in the gut of scabies mites in skin burrows. We propose that SMIPP-Ss minimize complement-mediated gut damage and thus create a favorable environment for the scabies mites.