Résumé : Since a few years, the international economic system has been experiencing growing fragmentation and uncertainty. However, research on Regional Innovation Systems (RIS) has yet to comprehensively engage with this phenomenon, despite its (spatial) significance. The paper contributes to addressing this gap, in particular by exploring the potential implications for RIS arising from the decline and disruptions of international knowledge flows associated with economic de-globalization. The study seeks to define a theoretical approach grounded in evolutionary geography to assess this trend. It applies such perspective to three types of RIS—metropolitan, old industrial, and peripheral—across five analytical dimensions that capture the structural and relational factors shaping RIS exposure and resilience to de-globalization. The discussion highlights that, in the face of knowledge and technological disruptions arising from international instability, metropolitan RIS may leverage their diversified knowledge bases, dense institutional frameworks, and strong global connectivity to successfully reconfigure external linkages; old industrial RIS may follow mixed trajectories, with the risk of deepening economic and policy lock-ins; while peripheral RIS—due to their reliance on external knowledge sources and limited endogenous innovation capacity—emerge as the most vulnerable.