Smart Specialisation Strategy is a place-based EU policy that seeks to enhance regional competitiveness through leveraging and bolstering innovation in the selected priority areas (industries or technologies) in each region. The new iteration of S3 requires developing cross-border collaborations with regions possessing complex and complementary technological expertise currently missing in a region to upgrade its technological evolution. The reason for this is that new growth opportunities arise from recombining existing technological capabilities while more complex technologies offer strong competitive advantage. This paper presents a simple roadmap for regional S3 internationalisation and the results of an in-depth case study on the opportunities for and barriers to S3 internationalisation in Friuli Venezia Giulia (FVG), a region in the North East of Italy. The paper develops recommendations on how to make the most of the Research, Technology, Development and Innovation endowments in FVG through enhancing the innovation-internationalisation nexus in order to improve competitiveness of the region.