This paper provides a systematic approach for quantifying the influence of building size, construction category, climate, occupancy schedule, setpoint, and deadband on HVAC energy consumption in office buildings. Simulating the DOE reference office buildings of three sizes and three construction categories in all United States climate zones, using the EnergyPlus, we conducted several N-way ANOVA analyses to study the interrelationships between setpoints, deadbands and several building related and environment related factors. In summary, daily optimal deadband selection of 0, 1, 2, 4, 5, and 6 K would result in an average energy savings of -70.0, -34.9, -13.7, 9.6, 16.4, and 21.2 %, respectively, compared to baseline deadline of 3 K. Selecting the daily optimal setpoint in the range of 22.5 ± 1 °C, 22.5 ± 2 °C, and 22.5 ± 3 °C would result in an average savings of 7.5, 12.7, and 16.4 %, respectively, compared to the baseline setpoint of 22.5 °C. Additionally, we found that when the outdoor temperature is within -20 to 30°C, the optimal setpoint depends on the building size. We also observed a range of outdoor temperatures (e.g., 9 – 14 °C for small buildings and 8 – 11 °C for medium buildings) where the setpoint selection would only slightly influence the energy consumption. However, the choice of setpoints becomes very influential (up to 30% of energy savings) where the outdoor temperatures are slightly outside the mentioned ranges on either direction. The potential savings from selecting daily optimal setpoints in the range of 22.5 ± 3 °C in different climates and for small, medium and large office buildings, would lead to 10.09 – 37.03%, 11.43 – 21.01%, and 6.78 – 11.34 % savings, respectively, depending on the climate.