Complement opsonization is among the biggest challenges facing nanomedicine. Nearly instantly after injection into blood, nanoparticles are opsonized by the complement protein C3, leading to clearance by phagocytes, fouling of targeting moieties, and release of anaphylatoxins. While surface polymers such as polyethylene glycol (PEG) partially decrease complement opsonization, most nanoparticles still suffer from extensive complement opsonization, especially when linked to targeting moieties. To ameliorate the deleterious effects of complement, we have conjugated two of mammals’ natural regulators of complement activation (RCAs), Factors H & I, to the surface of nanoparticles. In vitro, Factor H or I conjugation to PEG-coated nanoparticles decrease their C3 opsonization, and markedly reduce nanoparticle uptake by phagocytes. In an in vivo mouse model of sepsis-induced lung injury, Factor I-conjugation abrogates nanoparticle uptake by intravascular phagocytes in the lungs, allowing the blood concentration of the nanoparticle to remain elevated much longer. For nanoparticles targeted to the lung's endothelium by conjugation to anti-ICAM antibodies, Factor I-conjugation shifts the cell type distribution away from phagocytes and towards endothelial cells. Finally, Factor I-conjugation abrogates the severe anaphylactoid responses common to many nanoparticles, preventing systemic capillary leak and preserving blood flow to visceral organs and the brain. Thus, conjugation of RCAs, like Factor I, to nanoparticles is likely to help in nanomedicine's long battle against complement, improving several key parameters critical for clinical success.