This paper investigates the possible presence of three problems in regional innovation systems (RIS): intermediation, reciprocity and compatibility. Based on firm data gathered for three different regions, Northern Hesse, Jena and Sophia Antipolis, we can show that a low propensity to cooperate in a RIS is related to poorly performing intermediaries and a low complementarity with the regional knowledge base. The issue of trust in cooperating tends to have no effect on the propensity to cooperate. However, it is a main determinant of failed cooperation projects.