A wall-return ventilation system, containing ceiling-supply and wall-return air grilles, is traditionally used in non-unidirectional airflow cleanrooms. In such a wall-return cleanroom, the pathways of return airflow towards the wall-return grilles may be affected by locations and layouts of the production lines and tool equipment; moreover, especially considering the needs for relocation of production lines and rearrangement of tool equipment in the industrial cleanrooms, this study proposed a fan dry coil unit (FDCU) return system, containing ceiling-supply and ceiling-return air grilles, and conducted experimental works in a full-scale cleanroom to investigate the performance of the innovative and traditional ventilation systems. The influences of air change rates and supply air plenum pressures on the removal of 0.1 μm particles were examined in the experiment. Results presented in this paper were subject to the particle size of 0.1 μm. The FDCU-return ventilation arrangement may provide viable solutions to effective contamination control. The results showed that the innovative FDCU-return system can effectively eliminate about 50% of 0.1 μm particles from the cleanrooms more than the conventional wall-return system. Moreover, the outcomes from this study suggested that particle removal rates for the given cleanrooms were significantly affected by air change rates.