Development of regional innovation system (RIS) and its role in regional development is a debated research topic. Most of the theoretical and empirical works are traditionally focused on RIS situated within a national context and applies institutional theory. Recently the application of RIS concept was debated in relation to cross-border settings. Extending this line of research, we aim to study the role of entrepreneurship in one particular industry – cleantech – in the development of a cross-border RIS using the example of Øresund, Swedish-Danish transnational region. Eighteen interviews with regional stakeholders related to academia, business and administration were conducted. Our findings reveal that in order for innovations in cleantech to be realised, the efforts of entrepreneurs are necessary to promote knowledge spillover from research institutes and ‘locked’ systems into business environments. Further, encouraging research-based innovations related to social sciences significantly extends the possibility of building robust RIS.