A methodology to assess seismic fragility of a nuclear power plant (NPP) using a conditional mean spectrum is proposed as an alternative to using a uniform hazard response spectrum. Rather than the single-scenario conditional mean spectrum, which is the conventional conditional mean spectrum based on a single scenario, a multi-scenario conditional mean spectrum is proposed for the case in which no single scenario is dominant. The multi-scenario conditional mean spectrum is defined as the weighted average of different conditional mean spectra, each one of which corresponds to an individual scenario. The weighting factors for scenarios are obtained from a deaggregation of seismic hazards. As a validation example, a seismic fragility assessment of an NPP containment structure is performed using a uniform hazard response spectrum and different single-scenario conditional mean spectra and multi-scenario conditional mean spectra. In the example, the number of scenarios primarily influences the median capacity of the evaluated structure. Meanwhile, the control frequency, a key parameter of a conditional mean spectrum, plays an important role in reducing logarithmic standard deviation of the corresponding fragility curves and corresponding high confidence of low probability of failure (HCLPF) capacity.