A large number of studies have emphasized the spatial proximity of economic activity and its relation to the spatiality of knowledge creation in various types of connections. Far less attention has been paid to the understanding of the determinants of ‘cultural’ and geographical proximity in international R&D cooperation projects involving SMEs and the role of the quality of the Regional Innovation System (RIS). Using a database of completed European Cooperative Research projects, we conclude that: 1) technologically more complex projects are more likely to involve ‘culturally’ and geographically distant partners; 2) RIS related variables determine ‘cultural’ proximity but not geographical proximity; 3) at first sight surprisingly, international cooperation projects involving the 1st promoters of innovation-led regions (high patent propensity and high human capital levels) are culturally more distant.