Research studies provided evidence on the energy efficiency of integrating personal thermal comfort profiles into the control loop of Heating, Ventilation, and Air-Conditioning (HVAC) systems (i.e., comfort-driven control). However, some conflicting cases with increased energy consumption were also reported. Addressing the limited and focused nature of those demonstrations, in this study, we have presented a comprehensive assessment of the energy efficiency implications of comfort-driven control to (i) understand the impact of a wide range of contextual factors and their combinatorial effect and (ii) identify the operational conditions that benefit from personal comfort integration. In doing so, we have proposed an agent-based modeling framework, coupled with EnergyPlus simulations. We considered five potentially influential parameters and their combinatorial arrangements including occupants’ thermal comfort characteristics, diverse multi-occupancy scenarios, number of occupants in thermal zones, control strategies, and climate. We identified the most influencing factor to be the variations across occupants’ thermal comfort characteristics - reflected in probabilistic models of personal thermal comfort - followed by the number of occupants that share a thermal zone, and the control strategy in driving the collective setpoint in a zone. In thermal zones, shared by fewer than six occupants, we observed potentials for average energy efficiency gain in a range between −3.5% and 21.4% from comfort-driven control. Accounting for a wide range of personal comfort profiles and number of occupants, the average (±standard deviation) energy savings for a single zone and multiple zones were in ranges of [−3.7 ± 4.8%, 5.3 ± 5.6%] and [−3.1 ± 4.9%, 9.1 ± 5.1%], respectively. Across all multi-occupancy scenarios, a range between 0.0% and 96.0% of combinations resulted in energy savings.