High-temperature synthesized monodisperse superparamagnetic iron oxide nanoparticles are obtained with a strongly bound ligand shell of oleic acid and its decomposition products. Most applications require a stable presentation of a defined surface chemistry; therefore, the native shell has to be completely exchanged for dispersants with irreversible affinity to the nanoparticle surface. We evaluate by attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and thermogravimetric analysis/differential scanning calorimetry (TGA/DSC) the limitations of commonly used approaches. A mechanism and multiple exchange scheme that attains the goal of complete and irreversible ligand replacement on monodisperse nanoparticles of various sizes is presented. The obtained hydrophobic nanoparticles are ideally suited for magnetically controlled drug delivery and membrane applications and for the investigation of fundamental interfacial properties of ultrasmall core-shell architectures.