The importance of inter-regional co-operation and innovation are widely accepted in the development rhetoric of the European Union. The highlighted importance of both themes in the context of borderlands has recently led to the coining of a new concept, cross-border regional innovation system. However, little attention has been given to the empirical analysis of the concept. This paper suggests a framework for empirically validating the concept by examining the levels of integration between cross-border regions. The outcome is a proposed framework that can be operationalised by measurable indicators of cross-border co-operation in a regional innovation system setting. The framework was further tested with illustrative empirical cases that demonstrate its feasibility.