The clearance of colloidal particles from the blood circulation occurs by phagocytes and/or endothelial cells, mainly in the liver, the spleen, and the bone marrow. The relative distribution of the injected particles in these organs is known to depend on various factors such as the size and surface properties of the particles and the type of serum proteins adsorbed onto the surface of particles. The basic principles behind their distribution characteristics into the reticuloendothelial system, however, remain unclear. This article reviews major determinants in hepatic disposition of polystyrene nanospheres, especially the relationship among physicochemical properties of the particle surface, the type of blood components associated onto the surface of particles, and their in vivo disposition characteristics in rats, and considerations to be given and implication for the rational design of particulate drug carriers are discussed.