The use of upper room ultraviolet germicidal irradiation (UR-UVGI) has been proven to be an effective and energy efficient method for minimizing bacterial and viral disease transmission in indoor environments. The aim of this paper is to investigate numerically the performance of UR-UVGI in three different ventilation systems: mixing, downward, and displacement ventilation. A detailed three-dimensional computational fluid dynamics (CFD) model is developed in the Eulerian domain to simulate the dispersion and UV inactivation of Staphylococcus aureus, a common type of airborne bacteria, in a two-bed patient room. The room is simulated with and without the presence of UR-UVGI for each of the concerned ventilation systems while the bacteria generation and air exchange rate remain unchanged in all simulated cases. Results revealed that UR-UVGI can achieve an efficacy of 99.8% in the occupied zone of both mixing and downward ventilation systems when a UV output of 36 W is delivered to the room, whereas an efficacy of 78% is achieved in the case of displacement ventilation.