Over the past decades, the EU heavily invested in Research Infrastructures (RI). What are the expected returns of such investments? In the present article we address the question of returns on public funds/public infrastructures. We consider the role of RI and universities from an economic, social, and entrepreneurial perspective from various Territorial Innovation Models (TIMs): (1) Italian industrial districts, (2) innovative milieus, (3) regional innovation systems, (4) new industrial spaces, and (5) regional clusters. We conducted our empirical study on Grenoble Isère Alpes Nanotechnologies (GIANT), which is composed of large scientific instruments, universities, and engineering and management schools. Our microeconomic methodology measured the socioeconomic and entrepreneurial effects of GIANT with respect to budget, employment, and spin-off generation. We contribute to the existing body of knowledge on TIMs by (1) comparing the long-term investments to the generation of wealth, the creation of employment, and the development of start-ups; (2) adding new insights to the debate opposing positive and negative impacts empirical studies; and (3) offering recommendations for the use of public resources. In our discussion, we compare the GIANT model as a very localized RI-university club to the Grenoble model as localized cluster.