The IFMIF-DONES project is undertaking the design and construction of a scientific facility near Granada, Spain, intended for the irradiation of fusion materials under a neutron spectrum similar to that found inside a nuclear fusion reactor. Granada is a moderately seismic region within the Iberian Peninsula, which requires an appropriate seismic design strategy to ensure the reliable and safe operation of the facility.The Main Building, which houses the facility's critical systems, consists of a concrete structure seismically isolated from the ground. As the project progressed, more detailed in-situ investigations and a comprehensive Seismic Hazard Assessment refined the understanding of site conditions. These updated analyses suggested that seismic base isolation may not be strictly necessary from a structural perspective and could introduce additional construction complexities. This has enabled the consideration of alternative foundation schemes, although these may influence the performance of the installed equipment.This study presents the results of structural analyses for several substructure options without seismic isolation, including ground improvement techniques and the use of piles. The alternatives are compared based on their impact on the overall building design and the seismic demand transmitted to sensitive internal components, as represented by the Floor Response Spectra (FRS), providing a trade-off analysis of performance and constructability. Finally, for the best-performing alternative, probabilistic FRS are derived to quantify the impact of soil variability on seismic demand.