Small-medium reactors (SMRs) are going to be important players in the worldwide nuclear renaissance. The economy of scale plays against the development of this kind of reactors, even if sometimes its influence is overestimated so that SMRs appear to have a levelized unit electricity cost significantly higher than large reactors (LRs). However, the economy of scale applies only if SMR designs are similar to that of LRs, but this is not the case since the small size allows for original design solutions not accessible to large sized reactors. The literature already presents studies showing how, under certain assumptions, the capital cost and the operation and maintenance cost of a site provided by one large reactor is quite similar to another site composed of four SMRs providing the same power output. However, the literature still lacks this kind of analysis on the decommissioning cost. The paper fills this gap, investigating the cost breakdown of a decommissioning project and providing a literature review about its cost estimate techniques and managerial approach. This paper identifies and briefly discusses the different cost drivers related to the decommissioning phase of a nuclear plant focusing the attention on those critical ones in the comparison between SMR and LR (economy of scale, multiple units in a single site, technical savings, and decommissioning strategy—“immediate decommissioning” or “deferred decommissioning”). The International Reactor Innovative and Secure reactor is used as the example of a SMR to quantify the effect of these drivers, but the analysis and conclusions are applicable to the whole spectrum of new small nuclear plants. The results show that when all of these factors are accounted for in a set of realistic and comparable configurations, and with the same power installed on the site, the decommissioning costs of a SMR with respect to a LR drop from three times higher to two times. If more than one large reactor is considered, the gap increases since the large reactor investment also reaps advantages from site sharing.