Seismic isolation systems have been extensively used in a number of critical structures to protect important civil infrastructure from risks posed by earthquakes. Despite the maturity of this technology, the application of seismic isolation to Nuclear Power Plant (NPP) facilities is quite limited. The effectiveness of the isolation system on NPPs has been questioned due to the significant and well-documented soil-structure interaction (SSI) effects on the response of large structures. The tendency of SSI to significantly shorten the predominant frequencies of the excitations felt by the heavy structure could reduce the effectiveness of isolation. On the other hand, base isolation leads to considerably lower frequency and significantly smaller base shear. Thus, the effect of SSI on seismically isolated NNPs is of great interest, since base isolation offers the opportunity to use existing standard designs in regions with higher seismicity. In this paper, an isolated NPP model is used to study the effects of soil-structure interaction effects on the seismic response of the system. Different ground motions are used to estimate the dispersion of the NPP response. Similarly, different soil profiles are examined parametrically to assess the influence of soil properties on the system behavior. The response of the isolated structure is compared to that of the conventional structure to illustrate the effectiveness of the seismic isolation system. Issues related to the numerical simulation of the problem are discussed as well.