Superparamagnetic iron oxide nanocrystals are a class of nontoxic and biodegradable nanomaterials with broad applications in science, engineering, and medicine, but there is still considerable debate on how crystalline domain size and surface chemistry influence their properties for magnetic resonance imaging (MRI). Here we examine the effects of particle size and surface chemistry by comparing proton relaxivity data for two particle sizes and three surface coatings (6 combinations). These combinations are achieved by using both direct ligand exchange and indirect encapsulation methods to solubilize oleic-acid capped iron oxide nanocrystals. The results indicate that proton relaxivity depends on the particle size, the surface coating thickness and hydrophilicity, and the coordination chemistry of inner capping ligands. Nanocrystals coated with the hydrophilic ligand polyethylenimine (PEI) yield the highest proton relaxivity, whereas nanocrystals capped with oleic acid and amphiphilic polymers exhibit the strongest dependence on particle size. These effects arise from intrinsic surface spin disorders as well as from rapid exchange (diffusion) of water molecules between the bulk phase and the adjacent layer surrounding the particle surface.