Any operation addressing historical buildings refurbishment and plant system retrofitting is a complex task. Here we propose a methodological approach for achieving efficient, sustainable energy solutions guarantying objectives of conservation and preventive protection of the Cultural Heritage as well as Indoor Air Quality (IAQ) and thermal comfort for the users. As a consequence, all the related operations should be efficient and effective, in compliance with required indoor thermo-hygrometric conditions, ventilation, air quality and user wellbeing. La Montagnola primary school in Florence, designed by the architect Francesco Tiezzi and built between 1958 and 1963 is the case study. Dynamic simulations specifically addressed to control and adaptive proportional regulation of the building-plant system. Results showed that refurbishment and retrofitting operations on the plant system led to more significant energy saving in comparison with that obtained only with interventions on building envelope, mainly under constraints imposed by the National Heritage Protection Offices (Soprintendenza). Results assessment highlighted the fact that the use of dynamic simulation and CFD techniques, and consideration of thermal comfort at an early design stage, allowed the identification of design solutions combining energy saving with internal comfort, health and safety during throughout the school year.