The main purpose of Heating, Ventilating and Air-Conditioning (HVAC) systems is to satisfy thermal comfort for the occupants. Conventionally, HVAC systems adjust set-temperature to achieve thermal comfort by continuously measuring indoor air temperature of the environment. However, ASHRAE 55, a standard of acceptable thermal environments, offers to use acceptable ranges of operative temperatures in air-conditioned buildings. Considering operative temperature is a function of indoor air temperature and mean radiant temperature, set-temperature of HVAC system can be controlled by using operative temperature to satisfy neutral thermal comfort for the occupants. This study compares thermal comfort and energy consumption of two exactly same HVAC systems which are operated based on indoor air temperature and operative temperature, respectively. Two office rooms with same architectural configurations -which are located in a university-Ankara-Turkey- were selected as a case study. The HVAC systems were operated based on indoor air temperature and operative temperature, respectively, at the same time and occupancy schedules. The results showed that operative temperature driven controlled HVAC system achieves better thermal comfort while slightly increasing energy consumption. The main findings of this study would be useful not only to design energy-efficient HVAC systems but also create more comfortable environments.