Earth-to-air (EAHX) and/or air-to-air (AAHX) heat exchangers can be conveniently inserted in heating, ventilation, and air conditioning (HVAC) systems to obtain relevant energy saving. In this article, the subject is analyzed for an office building located in two Italian localities: Milan (Northern Italy, with cold winters and hot summers) and Palermo (Southern Italy, with mild winters and very hot summers). A dynamic building energy performance simulation software is used to simulate a designed office building. The HVAC system is based on fan-coils and primary air, with or without EAHX and AAHX. The seasonal analysis shows better energy results for AAHX in winter and EAHX in summer, respectively. The yearly analysis shows that the EAHX is preferable in hot or mild climates. Successively, the EAHX and AAHX are combined: based on the previous seasonal results, the first one is activated in summer, while the second in winter. The combination of the two technologies is preferable for Milan (energy saving up to about 75%) compared to Palermo (saving up to about 60%). Finally, the analyses of the equivalent CO2 emissions and discounted payback are reported.