Monodisperse mesoporous silica (mSiO2) coated superparamagnetic iron oxide (Fe3O4@mSiO2) nanoparticles (NPs) have been developed as a potential magnetic resonance imaging (MRI) T2 contrast agent. To evaluate the effect of surface coating on MRI contrast efficiency, we examined the proton relaxivities of Fe3O4@mSiO2 NPs with different coating thicknesses. It was found that the mSiO2 coating has a significant impact on the efficiency of Fe3O4 NPs for MRI contrast enhancement. The efficiency increases with the thickness of mSiO2 coating and is much higher than that of the commercial contrast agents. Nuclear magnetic resonance (NMR) relaxometry of Fe3O4@mSiO2 further revealed that mSiO2 coating is partially permeable to water molecules and therefore induces the decrease of longitudinal relaxivity, r1. Biocompatibility evaluation of various sized (ca. 35–95 nm) Fe3O4@mSiO2 NPs was tested on OC-k3 cells and the result showed that these particles have no negative impact on cell viability. The enhanced MRI efficiency of Fe3O4@mSiO2 highlights these core–shell particles as highly efficient T2 contrast agents with high biocompatibility. Copyright © 2012 John Wiley & Sons, Ltd.