Heating, ventilation, and air-conditioning (HVAC) systems usually have a set-point temperature control feature that uses the indoor dry-bulb temperature to control the indoor environment. However, an incorrect set-point temperature can reduce thermal comfort and result in unnecessary energy consumption. This study focuses on a derivation method for the optimal cooling set-point temperature of an HVAC system used in office buildings, considering the thermal characteristics and daily changes in the weather conditions, to establish a comfortable indoor environment and minimize unnecessary energy consumption. The operative temperature is used in the HVAC system control, and the mean radiant temperature is predicted with 94% accuracy through a multiple regression analysis by applying the indoor thermal environment data and weather information. The regression equation was utilized to create an additional equation to calculate the optimal set-point temperature. The simulation results indicate that the HVAC system control with the new set-point temperatures calculated from the derived equation improves thermal comfort by 38.5% (26%p). This study confirmed that a cooling set-point temperature that considers both the thermal characteristics of a building and weather conditions is effective in enhancing the indoor thermal comfort during summer.