Nanoparticles are increasingly important for biological applications ranging from drug delivery to cellular imaging. In the course of these applications, nanoparticles are exposed to a complex environment of extracellular proteins that can be adsorbed onto the surface of the nanoparticle, altering nanoparticle-cell interactions. We have investigated how proteins found in blood serum affect the binding of nanoparticles to the surface of cells. Using fluorescence microscopy, we find that the cellular binding of cationic nanoparticles is enhanced by the presence of serum proteins, while the binding of anionic nanoparticles is inhibited. We have determined that this difference in cellular binding is due to the use of distinct cellular receptors. Competition assays, quantified with flow cytometry, show that the protein-nanoparticle complex formed from the cationic nanoparticles binds to scavenger receptors on the cell surface. Interestingly, the protein-nanoparticle complex formed from anionic nanoparticles binds to native protein receptors. As nanoparticles become increasingly important for in vivo applications, we expect these results will inform the design of nanoparticles with improved cellular binding.