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This paper elaborates a view on knowledge as a result of a combinatorial search activity, so as to investigate its effects on economic growth at the regional level. Empirical estimations corroborate the hypothesis that knowledge coherence and variety, besides the traditional measure of knowledge stock, matter in shaping regional economic performances. The check for spatial dependence suggests that cross-regional externalities exert additional triggering effects on growth, without debasing the effects of knowledge properties. Important policy implications stem from the analysis, in that regional innovation strategies should be carefully coordinated so as to reach a higher degree of internal coherence and trigger economic performances.