Several factors related to germicidal ultraviolet fixtures, HVAC layout, and the resulting airflow flow patterns can affect the performance of upper-room ultraviolet germicidal irradiation (UVGI) applications. With the help of Computational Fluid Dynamics (CFD) analyses, this study systematically evaluated the impact of the HVAC layout on the effectiveness of the upper room UVGI system for an overhead mixing system. The results indicate that the room airflow patterns resulting from the variations in the layout of 4-way diffusers and returns can have a little impact on the overall effectiveness of the upper-room UVGI system. However, these analyses show subtle differences in the nature of airflow patterns and their impact on UV-C effectiveness. The stagnant zones with recirculating airflow patterns, if formed in the vicinity of an infected individual and under the high UV-C intensity zone, can reduce the probability of infection. Since a location of an infected individual is not known a priori, the aerodynamic containment layout with the distributed supply and distributed returns can help in maximizing both the ventilation effectiveness as well as the UV-C effectiveness.