In order to obtain water-soluble Fe3O4 nanoparticles (NPs), fast ligand exchange method was applied to make hydrophobic oleic acid coated Fe3O4 NPs turn into water-soluble PEG [PEG = poly(ethylene glycol)] phosphate coated Fe3O4 NPs using PEG phosphate as the hydrophilic ligand in toluene/tetrahydrofuran (THF)/water ternary mixed solvent system. The effect of THF on the ligand-exchange rate was studied. The NPs were characterized by means of TEM, DLS, XRD, FTIR and VSM, respectively. Results showed that THF solvent could promote effective contact of PEG phosphate molecules with the surface of Fe3O4 NPs, and make oleic acid molecules rapidly desorbe from the surface of the NPs, in addition, they eliminated the emulsification during the ligand exchange process. A rapid ligand exchange method used to prepare the water-soluble PEG phosphate coated Fe3O4 NPs was achieved by using of THF solvent.