The regional knowledge creation is the dominant economic explanation of regional competitiveness. In view of this, the commercialization and diffusion of knowledge/technology, developed in academia, have increased the attention of policy makers as strategic and key element, supporting and fostering the regional socio-economic development and competitiveness. University spin-offs (USOs), companies created to exploit the knowledge and technology developed within a university, are a potential and active way to stimulate the knowledge growth of economies in different regional contexts. The paper tests the hypothesis that USOs may partly determine the competitive advantage of the regions. Based on a longitudinal sample of 952 USOs located in 20 Italian administrative regions and by applying 6 linear-mixed models, the results show that USOs effectively contribute in fostering regional competitiveness only in terms of number (count) of USOs from a given university, while the effect of their patent activity is weak. On the basis of the results, some remarkable theoretical, managerial, and policy implications are advanced.