<p>The purpose of this paper is to evaluate which universities spin out biotechnology SMEs, and why some do this successfully while others do not. The research question is: <i>how do institutional, contextual, and geographic factors shape biotechnology spin-out activity among UK universities?</i> A systematic review was carried out, which examined data from the websites of 26 UK universities in 10 geographic regions and 4 industry bodies. To supplement this review, a questionnaire was used to evaluate the factors which encourage universities to spin out. The results show that biotechnology spin-outs tend to be clustered around certain geographical locations. This clustering activity is not deliberate and exists as a by-product of activity. Interestingly, certain universities with good research backgrounds have been shown to produce little to no biotechnology spin-outs. Six themes were noted as drivers for the creation of biotechnology university spin-outs: increased support from universities; funding opportunities; research excellence framework and knowledge exchange framework metrics and impact; geographical location of universities; revenue and profit; a push on technology transfer and intellectual property. The geographical advantage of being near a biotechnology cluster is clear. However, by building a solid research base with an international reputation, a supportive Technology Transfer Office, education for academic staff in entrepreneurial attributes and behaviours, and engaging with biotechnology accelerators, a university can enhance its spin-out success rate even when that university does not have the benefit of geography and a close regional cluster.</p> Graphical Abstract <p></p>