Business interaction is important for innovation performance but may be challenging in cross-border regions. The objective of this research was to investigate the relation between factors that define cross-border business interaction and innovativeness. From the cross-border regional innovation systems literature, we operationalized thirty-five factors which potentially influence cross-border business interaction; these factors concern availability of science and knowledge bases, socio-cultural proximity, accessibility, institutional set-up, and governance. We conducted a survey focusing on these factors and analyzed the data using Cronbach's alpha and linear regression. The cross-border interaction factors identified in the survey results served as independent variables and the differences in innovativeness levels in different European cross-border regions served as our dependent variable. This study confirmed that differences in innovativeness levels between countries can be related to factors hindering cross-border business interaction.