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 labour 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 a Horizon 2020 project on lifelong learning policies for young adults that compares 18 regions in nine European countries. The data shows 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 highly segmented labour markets.