Buildings must provide Indoor Air Quality (IAQ) to the best of their ability while maintaining high energy efficiency. Mechanical ventilation systems are central to this concern. Despite the promises of innovative technologies in the market, a simple simulation tool for comparing their effects is not available. This article presents a TRNSYS-CONTAM co-simulation tool that enables the calculation of interdependent effects of temperature, moisture, and airflow on contaminant transport, and energy use on the building scale. The impact of the outdoor conditions, airtightness of building envelopes, neighboring environments, and the building’s wind exposure is also considered. IAQ is assessed by humidity, CO 2 concentration in the building, and the exposure of its occupants to PM2.5 and formaldehyde concentrations to comply with available recommendations. This paper presents the methodology employed to evaluate the global performance of ventilation systems in terms of energy efficiency and IAQ.