Past studies reveal that air infiltration through the building envelope and its impact on the indoor environment and energy consumption are significantly influenced by climate characteristics. However, little relevant information is available for buildings in southern China, where the building design traditionally follows a philosophy of being open and shaded. The present study employs both experimental measurements and numerical simulations to investigate the airtightness of buildings in Hot Summer and Cold Winter (HSCW) climate region of southern China and the associated energy consumption. The measurements and simulations are based on a typical office building in Changsha. Measurement results show that the air infiltration rate of six tested spaces at the natural pressure difference ranges from 0.10 to 0.30 h⁻¹ with an average of 0.17 h⁻¹ in summer, and from 0.09 to 0.32 h⁻¹ with an average of 0.16 h⁻¹ in winter. The operation of the air-conditioning system affects largely air infiltration, and each unit change in setpoint air temperature can result in an average of one-third or more change in air infiltration rate. Simulation results show that a decrease in air infiltration rate from 0.17 h⁻¹ to 0.01 h⁻¹ reduces the infiltration-related cooling energy consumption from 14.29 to 0.75 kWh/m²·year and heating energy consumption from 8.20 to 0.39 kWh/m²·year. The same change in the setpoint air temperature of air-conditioning system in summer and winter results in different infiltration-related energy consumption. The findings would contribute to an improved energy simulation and assessment of buildings in southern China.