Aedes aegypti is the main urban vector of dengue virus, chikungunya virus and Zika virus due to its great dispersal capacity and virus susceptibility. A. aegypti feed on plant-derived sugars but females need a blood meal for egg maturation. Haematophagous arthropods need to overcome host haemostasis and local immune reactions in order to take a blood meal. In this context, molecules present in the saliva and/or intestinal contents of these arthropods must contain inhibitors of the complement system (CS). CS salivary and/or intestinal inhibitors are crucial to protect gut cells of haematophagous arthropods against complement attack. The present work aimed to investigate the anti-complement activity of A. aegypti intestinal contents on the alternative, classical and lectin pathways of the human complement system. Here we show that A. aegypti gut contents inhibited the human classical and the lectin pathways but not the alternative pathway. The A. aegypti gut content has a serine protease able to specifically cleave and inactivate human C4, which is a novel mechanism for human complement inactivation in haematophagous arthropods. The gut of female A. aegypti was capable of capturing human serum factor H (a negative complement modulator), unlike males. C3 molecules in recently blood-fed female A. aegypti remain in their original state, being inactivated to iC3b soon after a blood feed. A transmission-blocking vaccine using these complement inhibitory proteins as antigens have the potential to interfere with the insect’s survival, reproductive fitness and block their infection by the arboviruses they transmit to humans.Copyright © 2020 Elsevier Ltd. All rights reserved.