This paper investigated the influence of diffuser layouts on the energy performance of stratified air distribution systems (STRAD). The energy saving potentials of STRAD systems are theoretically analyzed. The cooling coil load of a STRAD system is proportion to the return air temperature, while inversely proportional to the exhaust air temperature. Based on that, numerical studies are conducted for the applications of STRAD systems in three typical building space types. Two evaluation indices are developed to assess the energy performance of STRAD systems. The simulation results demonstrated that further energy saving could be achieved by keeping the exhaust grille at ceiling level and decreasing the height of return grille. Therefore, in order to optimize the energy saving capacity of STRAD systems, the return grille is recommended to be located as low as possible, whilst paying special attention on the “short-circuit” of cold supply air. Furthermore, when the STRAD system is applied in large space buildings with a big horizontal span, supply diffusers should be distributed surrounding the occupied zone as uniformly as possible, while avoiding installing return diffusers at exterior walls.