Three types of magnetic iron oxide nanoparticles with various kinds of surface modifications were synthesized, and the interactions between the nanoparticles and two types of high abundant plasma proteins were investigated by isothermal titration calorimetry and dynamic light scattering (DLS) methods. It was found that these interactions were strongly dependent on the surface properties of the nanoparticles. Enthalpy-entropy analysis suggested that poly(ethylene glycol) (PEG) modification on the particle surface could effectively reduce the interactions between the magnetic nanoparticles and the plasma proteins. DLS investigations further implied that electrostatic attractions could either increase or decrease the colloidal stability of the nanoparticles, depending on the particle surface properties, which will give rise to different in vivo biodistributions for the intravenously injected nanoparticles, according to literature reports. Proper surface modifications, upon the use of PEG in combination with various types of small molecules for reducing surface charges, were found to be effective for eliminating the strong interactions between nanoparticles and proteins, which is of the utmost importance for developing iron oxide magnetic nanoparticles with long blood circulation time for in vivo applications.