This article compares two contrarily complementary European cross-border city-region case studies from the social innovation multidisciplinary viewpoint. To do this it applies the ‘5-System’ city-region analytical framework presented sequentially at the RSA 2013 Winter Conference in London (Calzada, 2013) and the RSA 2014 European Conference in Izmir (Calzada, 2014). The Basque Country (OECD, 2013) nationalistic city-region (Calzada, 2011), divided between the Spanish and French nation-states, shows surprisingly low cross-border territorial development strategic synergies. In contrast, the Øresund non-nationalistic city-region (OECD, 2003) shows a highly cooperative and fluent cross-border dynamic that started in 2000. Analysed purely from the city-regional strategic perspective, Øresund, through its non-nationalistic city-regional promotion, has attained a certain level of cross-border territorial synergy between Malmö and Copenhagen; meanwhile, the Basque Country, also involving two nation-states but driven by a nationalistic political strategy, has failed to connect with and benefit from the cross-border territorial synergies between Spain and France, and even indeed between the two administrative entities in Spain.