Scale-up of high-shear granulation has been an important yet challenging issue in the pharmaceutical industries. A discrete element method (DEM) is a promising tool for the rational design and scale-up of high-shear granulation, because the internal properties such as particle flow and stress field, which are hard to measure experimentally, can be investigated. This chapter presents application of DEM to the scale-up of high-shear granulation. First of all, a brief introduction of DEM is described. Physical properties that we need to analyze for the scale-up of high-shear granulation are then discussed, and advantages of DEM to the scale-up issue are presented. Subsequently, calculation outputs that we should/can extract from DEM simulation are summarized from the viewpoint of geometric, kinematic, and dynamic similarities. Finally, some application examples are reviewed.