The rapid clearance of intravenously administered nanoparticles (NPs) from the bloodstream is a major unsolved problem in nanomedicine. Here, we describe the first use of biocompatible protein-avoidant ionic liquids (PAILs) as NP surface modifiers to reduce opsonization. An ionic liquid choline hexenoate, selected for its aversion to serum proteins, was used to stably coat the surface of poly(lactic--glycolic acid) (PLGA) NPs. Compared with bare PLGA and poly(ethylene glycol)-coated PLGA particles, the PAIL-PLGA NPs showed resistance to protein adsorption in vitro and greater retention in blood of mice at 24 hours. Choline hexenoate redirected biodistribution of NPs, with preferential accumulation in the lungs with 50% of the administered dose accumulating in the lungs and <5% in the liver. Lung accumulation was attributed to spontaneous attachment of the PAIL-coated NPs on red blood cells in vivo. Overall, ionic liquids are a promising class of materials for NP modification for biomedical applications.