Abstract: The influence of the initial structural characteristics of loess on the stability of three-dimensional (3D) slopes under seismic loading remains to be further explored. To address this issue, an initial structural parameter of loess is introduced, and a method is proposed for calculating the seismic safety factor of 3D loess slopes with varying initial structures. The pseudo-static method is used to characterize the seismic load. Meanwhile, an instability coefficient is introduced to establish a unified 3D failure mechanism, enabling a consistent description of different slope failure types, including toe failure, face failure, and base failure. Based on the work-energy balance equation, an analytical solution for the seismic safety factor of 3D loess slopes considering initial structural effects is derived. A hybrid optimization method is further utilized to obtain the optimal safety factor. The comparisons with existing studies validate the effectiveness of the method proposed. Additionally, parametric analyses are conducted to investigate the influence of initial structural parameters, of seismic loading, and of geometric factors on slope stability and on the characteristics of the critical slip surface.