Italy’s long seismic history continues to offer important lessons in preparedness, response, and recovery. However, both past and recent events have revealed the poor seismic performance of many buildings, highlighting the severe consequences of inadequate resilience to seismic hazards. This situation often leads to post-earthquake scenarios where, due to extensive damage, structures are difficult to repair or in need of demolition/reconstruction, causing considerable socio-economic losses. In addition, such damage requires extensive repair operations, leading to large CO2 emissions, tons of debris, relocation and reconstruction, significantly impacting the environment. In this context, structural safety and environmental sustainability are crucial in reducing the losses associated with both seismic and climate change impacts. Although the need for integrated rehabilitation/retrofit strategies increasingly emerged in recent years, there is still the need for implementation of technologies for combined seismic and energy loss reduction. Within this context, the SMART project aims at developing a methodology to assess integrated seismic and energy losses. To achieve these objectives, an existing case-study Reinforced Concrete (RC) structure, representative of the widespread RC buildings in Italy built prior to modern seismic codes, was selected. Two contextual scenarios are defined to simulate different seismic and thermal response conditions and various retrofitting solutions are compared with the aim of minimizing combined seismic and energy losses. As a preliminary step, this paper presents the design and modelling of the case-study structure and provides an initial assessment of its seismic performance in two contextual scenarios (i.e., low and high seismicity). Finite Element (FE) models are developed in SeismoStruct and SAP2000, including the contribution of both structural and non-structural elements. Non-linear static and dynamic analyses are performed and compared to evaluate the seismic performance of the structure, both its original state and after the application of two retrofitted strategies. Subsequently, the Expected Annual Losses (EAL) are assessed and compared to provide a preliminary probabilistic comparison of the results.