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• Investigated climate change impacts on office building performance in Brussels. • Applied a long-term climate change sensitive system sizing and design approach. • Time-integrated discomfort analysis showed a major surge in overheating by 2100. • Long-term climate change resistivity is ensured in reference building until 2100. • Primary energy use and GHG emission findings are useful in mixed humid climates. As climate change continues, it is expected that the risk of overheating will rise in both new and existing buildings in mixed humid climate zones in Europe. This study introduced a novel climate change sensitive sizing and design approach for cooling and heating systems in nearly zero-energy office buildings in Brussels, Belgium, for different weather scenarios. This approach considered the long-term effects of climate change on building performance. The climate change effects were assessed using current and future climate data from the regional atmospheric model, MAR. To demonstrate the approach, a case study of a nearly zero-energy office building in Brussels was conducted. The reference building model was first calibrated using monthly energy use data from the year 2019 using ASHRAE Guideline 14. Then, the building was evaluated with different HVAC strategies and their performances were quantified. The results indicated an increase in overheating as high as 1.2 °C and cooling energy use as high as 13.5 kWh/m2 and a decrease in overcooling as low as 0.3 °C and heating energy use as low as 10.9 kWh/m2 in the reference building by the end of the century. In addition, due to climate change sensitive sizing and design approach coupled with optimal sizing, the reference building was climate change resistant towards the worst-case scenario by end of the century with up to 3.7 for climate change overheating resistivity and 20.2 for climate change overcooling resistivity. Finally, the paper provided recommendations for future practice and research based on the study findings. [ABSTRACT FROM AUTHOR]