ABSTRACT We present a probabilistic seismic hazard analysis (PSHA) for the entire Po Plain sedimentary basin (Italy)—one of the widest Quaternary alluvial basins of Europe, to evaluate the impact of site-response characterization on hazard estimates. A large-scale application of approach 3 of the U.S. Nuclear Regulatory Commission (NRC) to include seismic amplification in the hazard is presented. Both 1D amplification related to stratigraphic conditions and 3D amplification due to basin effects are considered with the associated uncertainties, and their impact on the hazard is analyzed through a sensitivity analysis. Whereas 3D basin effects are considered through the application of an empirical, spatial invariant correction term, 1D amplification was estimated throughout the study area by means of dynamic (equivalent linear) ground-response analysis. To separate aleatory variabilities and epistemic uncertainties related to site response, a partially nonergodic approach is used. The results provide a finer picture of the actual seismic hazard, highlighting those areas where the ground motion is affected by amplification effects due to local or regional geological features. We found that, for a return period of 475 yr, neglecting basin effects produces a 30% underestimation of the seismic hazard in the long-period (>1 s) range. Moreover, with reference to the hazard model adopted, such effects are responsible for most of the epistemic uncertainty (up to 80%) in the results. Therefore, such effects deserve special attention in future research related to PSHA in the Po Plain sedimentary basin.