The management of natural risks is a complex endeavour, which encompasses a plurality of measures intervening at different stages. But given that resources to be dedicated to this endeavour are limited, choices need to be made among alternative measures, to ensure that risk management is both effective and efficient. One of the principal tools to make decisions concerning the best use of limited resources is cost-benefit analysis – a tool which, however, may be of limited use in contexts of severe uncertainty. In this paper, we identify the potential uncertainties that can play a role in the construction of a cost-benefit analysis, enriching the standard typology, and we present a plurality of approaches to address them. We illustrate our theoretical discussion of uncertainty by looking at a case study where cost-benefit analysis is used to assess alternative structural measures for seismic risk prevention.