AbstractExosomes are secreted nanometer‐sized vesicles derived from antigen‐presenting cells, which have attracted recent interest as they likely play important roles in immune regulation, and their use as cell‐free tools for immunotherapy has been proposed. Liposomes used clinically as transport vehicles can activate the complement system, leading to their rapid degradation and significant inflammatory toxicity. The use of isolated exosomes in therapy, therefore, may also elicit complement activation, reducing their potential efficacy. We have examined the expression and functional roles of the membrane regulators of complement (CD46, CD55 and CD59) on antigen‐presenting cell‐derived exosomes. Exosomes express the glycosylphosphatidylinositol (GPI)‐anchored regulators CD55 and CD59,but not the transmembrane protein CD46. Antibody blocking of CD55 in the presence of sensitizing antibody (w6/32) and human serum resulted in increased C3b deposition and significantly increased exosome lysis. Blockade of CD59 also resulted in significant lysis, while blocking both CD55 and CD59 increased lysis still further. We conclude that exosomes express GPI‐anchored complement regulators in order to permit their survival in the extracellular environment.