Reports of Intergovernmental Panel on Climate Change have set various greenhouse gas emissions scenarios, through which the evolution of the temperature of the planet can be estimated throughout the 21st century. The reduction of the emissions from the different activities carried out by mankind is crucial to mitigate greenhouse gas emissions. One of the most significant activities is users’ behaviour within buildings, particularly the use of Heating, Ventilation and Air-Conditioning systems. Modifying users’ behaviour patterns to guarantee acceptable thermal conditions inside buildings could lead to considerable energy saving percentages, and adaptive thermal comfort models could be an opportunity to achieve important savings. For this reason, this study analyzes the potential to apply adaptive thermal comfort models to use artificial air-conditioning systems by modifying setpoint temperatures. The analysis was conducted in five major European cities (Barcelona, Berlin, Bern, Rome, and Vienna) and in five climate change scenarios in the year 2050. The results showed that, in general, the energy saving achieved by adaptive strategies was larger in the cities with a greater cooling demand. Also, in both Representative Concentration Pathways (RCP) of the Fifth Assessment Report (AR5) considered, the energy saving were decreased in the cities of Barcelona and Rome, with values lower than those of the Fourth Assessment Report (AR4) scenarios considered, whereas in the cities of Berlin, Bern, and Vienna, the saving in the RCP scenarios is greater than those in the other scenarios.