Nanofluids have great potential to improve the heat transfer properties of liquids, as demonstrated by recent studies. This paper presents a novel idea of utilizing nanofluid. It analyzes the performance of a HVAC (Heating Ventilation Air Conditioning) system using a high-performance heat transfer fluid (water-glycol nanofluid with nanoparticles of Al2O3), in the university campus of Lecce, Italy. The work describes the dynamic model of the building and its heating and cooling system, realized through the simulation software TRNSYS 17. The use of heat transfer fluid inseminated by nanoparticles in a real HVAC system is an innovative application that is difficult to find in the scientific literature so far. This work focuses on comparing the efficiency of the system working with a traditional water-glycol mixture with the same system that uses Al2O3-nanofluid. The results obtained by means of the dynamic simulations have confirmed what theoretically assumed, indicating the working conditions of the HVAC system that lead to lower operating costs and higher COP and EER, guaranteeing the optimal conditions of thermo-hygrometric comfort inside the building. Finally, the results showed that the use of a nanofluid based on water-glycol mixture and alumina increases the efficiency about 10% and at the same time reduces the electrical energy consumption of the HVAC system.