Colloidal particles are good candidates for efficient drug carriers. However, the rapid clearance by macrophages of the reticuloendothelial system (RES), mainly Kupffer cells of liver and to a lesserextent macrophages of the spleen and the bone marrow, limits their application as carriers to other tissues and/or cells. To achieve a rational design of particulate carrier system, the basic information about in vivo disposition and the uptake mechanisms by RES of particle itself should be required. Therefore, in the present study, the in vivo disposition of polystyrene microsphere (MS) with the particle size of 50 nm (MS-50) or 500 nm (MS-500) was characterized after intravenous administration to rats. To study the mechanisms of the hepatic disposition of MSs, effects of serum on their disposition were investigated for both MSs by isolated liver perfusion experiments in rats. From these studies, it was found that serum would function both as opsonin to enhance the hepatic uptake of MSs and as inhibitor by reducing non-specific interaction between MSs and the plasma membrane. Whether serum promotes or inhibits the hepatic disposition of MSs would be dependent on the particle sizes of MSs.