HVAC systems are the major energy consumers in commercial buildings in the United States. Selection of setpoints impacts the amount of energy consumed by these systems. However, the influence of temperature setpoints on energy consumption and the potential energy savings are not yet fully identified. Through simulation this paper provides a systematic approach for quantifying the influence of different factors (i.e., construction category, climate, setpoint, and deadband) on building energy consumption. We implemented the approach on the medium-sized DOE reference office building of three construction categories in five climates using the EnergyPlus software. N-way ANOVA analysis ranked the factors as from the most influential to the least influential as: (1) construction category, (2) climate, (3) deadband, and (4) setpoint. Further analyses showed extending the deadband from 3 K to 6 K reduces energy consumption by 16.2%. Optimal annual setpoints varied across climates, and could lead to 6.63% average savings.