Structural differences regarding the presence of large firms are likely to influence the performance of Regional Innovation Systems. Regions lacking large firms to act as brokers of knowledge and coordinators of regional (R&D) collaboration may have to rely on other actors to form internal and external links. We investigate whether, in this case, universities can fulfill the needs of Small- and Medium-sized Enterprises (SMEs) with regard to coordination and knowledge flows. Using a data set of subsidized R&D collaborations, we compare universities' network positions in four model regions in Germany. Applying a Temporal Exponential Random Graph Model approach, we examine link formation and network structure with a focus on university–SME ties and their development over time. Results indicate that SMEs profit from connections to the university in all regions. Nevertheless, universities take more central roles in regions where the economic surrounding does contain fewer large firms as sources for knowledge exchange.