This research examines different experience of four European regions in generating dynamic spin-off activities. Based on case study research at four European universities – the University of Cambridge, UK; KU Leuven, Belgium; ETH Zurich, Switzerland; and TU Munich, Germany – we examine the relative importance of university as an institution in spin-off creation and the role of specific social and environmental factors that may hinder or foster the university spin-off process. We also examine the difference between various dimensions of spin-off process between the Anglo-Saxon and continental approach, the latter receiving, much less scholarly attention than the former. The results indicate that irrespective of the four locations the university spin-off process is significantly affected by university attributes such as university leadership, the degree of university’s entrepreneurial culture, access to university resources both inside and outside the university, stimulative incentive system, and engagement of professors as mentors or as academic entrepreneurs to graduates and would-be entrepreneurs. In addition, university’s close relationship with other entrepreneurial elements that together form an entrepreneurial ecosystem in which spin-offs can develop and flourish contributes not only to the development of the university entrepreneurial culture but also within the larger community, which positively reinforces that of universities and thus further enhances spin-off creation at universities. This analysis reveals quite distinctive outcomes regarding the characteristics of spin-off phenomenon between the Anglo-Saxon and Continental approach. The results indicate that the central mechanism in the emergence of high tech clusters is not necessarily the entrepreneurial activity, as has been often argued in the past. Instead, the emergence of high-tech clusters can be attributed to key individuals at the university or working in partnership with local players, which was the case at Leuven, Munich and Zurich. In addition, the findings suggests that support infrastructure and entrepreneurial recycling is not necessarily the by-product of spin-off phenomenon but is instead contingent on the active role of key individuals at the university and at local level, which again was the case at Leuven, Munich and Zurich. Finally, irrespective of the locations examined, the findings suggest the government plays an indispensable role in facilitating university spin-off creation.