In this study, we analyze the effect of the introduction of university regulations supporting academic entrepreneurship. Using a sample of 611 companies spun-off from the 64 Italian Science, Technology, Engineering, Mathematics and Medicine (STEMM) universities between 2002 and 2012, we show that university regulations in support of academic entrepreneurship have a positive effect on the creation of academic spin-offs. Nevertheless, their effectiveness is conditioned by specific contingencies. First, the characteristics of university departments influence the positive effect of the regulation: in some cases, there is a substitution effect rather than a complementary one. Second, the design of the regulation impacts the decisions of academic staff regarding whether to start a new venture. Finally, the effect of the regulation is maximized four years after its introduction and then becomes less effective. This paper contributes to the debate on the evaluation of policies supporting science-based entrepreneurship.