The use of pre-fabricated concrete components and their related coupling systems in seismic engineering constitutes a subject of wide and deep interest among researchers, practitioners and manufacturers all over the world, as demonstrated by a large number of studies conducted, among other Countries, especially in Japan, New Zealand and United States since the early ‘80s and, in relatively more recent times, in Italy. A key issue is given by the possibility to apply the typical benefits of the pre-fabrication not only to low rise industrial/commercial structures, but also to multi-storey frames for public and strategic buildings such as schools, hospitals and many others, as well as to high-rise residential premises built in areas characterized by a medium to high seismic intensity. On the basis of what stated above, an original structural system made by prefabricated composite steel truss-concrete beams and centrifuged high-strength concrete columns is presented in the following. Specifically designed joints are provided to couple the different structural components in order to guarantee an overall ease of construction with reduced tolerance problems and self-bearing capacity during temporary erection phases, with a consequent reduction in schedule and costs. The use of high performance concrete for columns allows for a high bearing capacity with limited overall dimensions and the consequent maximization of the commercial or saleable space. The original layout of the system proposed has led to the need to perform an intensive theoretical and experimental research activity. The finite element model of the structural system was calibrated upon both static and cyclic testing evidence carried out on full scale samples built in Italy and tested at the Tongji University-Shanghai, China. On the basis of the data collected, the tuned model was used to carry out further analyses and to deepen the specific knowledge on several further aspects, as specified in the following. Firstly, an estimation of the joint’s strength domain, suitable for everyday’s design was carried out based on a component-approach. Then, a structural optimization on the component used to guarantee hogging and sagging bending moment resistance to the joint, was carried out in order to achieve the minimization of the construction material employed. Furthermore, the estimation of the seismic performance of the joint, based on the evaluation of a purposely defined vulnerability parameter, supplied encouraging results with reference to the applicability of the investigated technology over most of the National territory. Finally an improved layout of the joint, with reference to confined concrete and the related possibility to achieve a suitable seismic response also at edge joints, is presented.