This study focuses on the investigation of the impacts of window operation on building performance for different types of ventilation systems including natural ventilation, mixed-mode ventilation, and conventional VAV systems in a medium-size office building. A building performance simulation tool—EnergyPlus—is used to simulate window operation for each system type. The investigation included the interaction between conventional VAV systems and window operation as well as control strategies for natural ventilation and mixed-mode ventilation. The results highlighted the impacts of window operation on energy use and comfort and identified substantial energy savings with mixed-mode ventilation during summer for various climates.