This paper investigates the regional innovation system (RIS) efficiency, and its determinants, in Italy through a Stochastic Frontier Analysis and using the concept of a knowledge production function. The contribution of universities’, private and public sectors’ resources devoted to research and development (R&D), in generating innovation, has been examined, as well as the impact of several exogenous environmental variables on RIS efficiency. The empirical findings suggest the importance of R&D investments taking place in the universities and in the private sector, which benefit the most to regional innovation activities; labour market and industries’ characteristics are found to have an important role on RIS efficiency