This paper explores the relationship between regional human capital (HC) and the processes of knowledge creation and mobilization due to Higher Education Institutions (HEIs). Although the nexus between these dimensions emerges frequently in both the scholarly and policy discourses, no study has so far investigated explicitly how their connection works. Using occupations as a proxy for the skill content of jobs, we analyse individual (gender, schooling and age) and regional (university orientation) factors that influence HC employment structure in Spanish regions over the period 2003-2010. The main finding is that teaching university mission is a robust predictor of high-skill employment, while the impact of engagement (research and knowledge transfer) activities is more sensitive to structural characteristics of the regional socio-economic context.