Maximizing energy efficiency within hospitals and healthcare facilities is a major challenge for sustainable development and energy saving objectives. In this study, the case study of the public hospital of Isernia (Italian backcountry city) is proposed, being typical of the hospital building stock developed in reinforced concrete all around Italy in the last 40 years. Starting from deep on-site investigations, based on direct surveys and documents, a transient energy model has been developed and calibrated, in order to reproduce the present scenario. This, in a next phase, has been modified for proposing a multi-target optimization of energy performances, by taking into consideration all main uses (heating, cooling, ventilation, lighting, domestic hot water), by refurbishing the building envelope, active energy systems and providing energy conversion from renewables. The whole energy retrofit, formulated on the basis of a multi-stage optimization problem, resulted technically efficient and economically feasible. Moreover, the peculiarities of the case study and of the method make that investigation repeatable with reference to both studying approach and outcomes.