The economic development of a territory is strongly correlated to its level of infrastructure (railway, roads, etc.); the complexity of this type of works requires careful planning and design that cannot be separated from the assessment of the impacts generated on citizenship affected by the new infrastructures. This study deals with the instrument defined by the Liguria Region for the implementation of infrastructures through the instruments called “Programmi Regionali di Intervento Strategico—P.R.I.S.” (Regional Strategic Intervention Programs) established by the Regional Law n. 39/2007. The aim of the P.R.I.S. is to guarantee the social protection of citizens that reside (as owners or tenants) or carry out economic activities in real estate units incompatible with the construction of the infrastructure, according to the main Italian law (Presidential Decree n. 327/2001) about the expropriation of private real estate for the construction of public works. In particular, the construction of a new link of the A7-A10-A12 motorway sections near the city of Genoa (called “Gronda”) is considered. The new infrastructure involves the expropriation of about 100 residential units and the relocation of about 50 production activities; the related P.R.I.S. defines the conditions that allow social cohesion through the recognition of indemnities for the expropriation of the real estate properties and the compensation of other expenses that the residents have to pay for their relocation. The valuation of the indemnities is developed through a multi-parameter model applicable for the estimation of real estate units (residential and productive) at a large-scale (mass appraisal); it is derived from the Market Comparison Approach and considers the most meaningful real estate characteristics. The aim is to develop a mass appraisal estimation model applicable in an easy way on real estate units with different destinations use. The model can be applied for the estimation of ordinary and special indemnities to be recognized for owners and tenants affected by the expropriation of their real estate units for the construction of public projects.