Given the sheer number of cross-border regions (CBRs) within the EU, their socio-economic importance has been recognized both by policy-makers and academics. Recently, the novel concept of cross-border regional innovation system has been introduced to guide the assessment of integration processes in CBRs. A central focus of this concept is set on analyzing the impact of varying types of proximity (cognitive, technological, etc.) on cross-border cooperation. Previous empirical applications of the concept have, however, relied on individual case studies and varying methodologies, thus complicating and constraining comparisons between different CBRs. Here a broader view is provided by comparing 28 Northern European CBRs. The empirical analysis utilizes economic, science and technology (S&T) statistics to construct proximity indicators and measures S&T integration in the context of cross-border cooperation. The findings from descriptive statistics and exploratory count data regressions show that technological and cognitive proximity measures are significantly related to S&T cooperation activities (cross-border co-publications and co-patents). Taken together, our empirical approach underlines the feasibility of utilizing the proximity approach for comparative analyses in CBR settings.