This article adopts the skill ecosystem approach to the comparative analysis of skill mismatch across European regions within different skill formation regimes. Institutional arrangements of skill formation regimes are designed at national level. However, they are enacted in regions with very different Labor market and socioeconomic conditions, which mediate the relationship between the institutional setting and its effects on the mismatch between the supply and demand of skills in a given region. Our analysis draws on quantitative and qualitative data from an EU Horizon 2020 project on lifelong learning policies for young adults that compares 18 regions in nine European countries. The data analyses show the importance of regional demand side factors in explaining skill shortages and skill surplus, and the coexistence of low-skill and high-skill equilibria in urban regions with high levels of skill polarization. Skill formation regimes present divergent effects on skill mismatch depending on the availability of jobs in the region and the level of skills demanded by the local economy. These findings suggest that combining skill formation regime and skill ecosystem approaches in comparative education research can provide better suited explanations of skill mismatch at regional and sectoral level.