This article explores the role of social capital in enabling knowledge transfer and exchange (KTE) between higher education institutions (HEIs) and spin-off (academic and non-academic) small and medium-sized enterprises in the context of open innovation, in order to convert knowledge into innovation within regional innovation systems. It presents the findings from 18 in-depth interviews with related stakeholders, and social network analysis of relationships in an exemplar technology park in Andalucía, southern Spain. The main findings suggest that there are many challenges to achieving successful KTE in regional innovation systems: recognition, intellectual property contracts and timescales. Similarly, there are opportunities related to intermediaries, joint teams and market impact. Significantly, the study highlights the importance of both formal and informal relationships as enablers of successful KTE involving HEIs and spin-off small and medium-sized enterprises in the context of open innovation.