An entrepreneurial university is a natural incubator that tries to provide a supportive environment in which the university community can explore, evaluate and exploit ideas that could be transformed into social and economic entrepreneurial initiatives. Entrepreneurial universities are involved in partnerships, networks and other relationships to generate an umbrella for interaction, collaboration and co-operation. Rapid developments in science, the multidisciplinary nature of frontier research, legislative changes such as the Bayh-Dole Act and demands from business and society have shaped knowledge-based entrepreneurship within universities. Despite sharing similar historical backgrounds, economic conditions and cultural and social structures, entrepreneurial universities in most countries remain distinct from one another by their institutional arrangements, traditions and characteristics unique to each organization. Interestingly, no comparative research has been conducted to understand the similarities and differences of the conditioning factors and the outcomes/outputs of entrepreneurial universities in different regions that share similar social, economic and political conditions. This paper addresses this research deficit, adopting institutional economics and resource-based view. We compare entrepreneurial universities in two European regions (Spain and Ireland) using an in-depth qualitative approach based on multiple case studies (two Spanish universities and two Irish universities) between 2006 and 2010. The findings provide organizational practices and approaches relevant to the transformation process of other regional universities seeking to become entrepreneurial.