Site response analysis is a precursor to soil-structure interaction analysis, which is an essential component in the seismic analysis of safety-related nuclear structures. Output from site response analysis provides input to soil-structure interaction analysis. Current practice in calculating site response for safety-related nuclear applications mainly involves the equivalent linear method in the frequency-domain. Nonlinear time-domain methods are used by some for the assessment of buildings, bridges and petrochemical facilities. Several commercial programs have been developed for site response analysis but none of them have been formally validated for large strains and high frequencies, which are crucial for the performance assessment of safety-related nuclear structures. This study sheds light on the applicability of some industry-standard equivalent linear (SHAKE) and nonlinear (DEEPSOIL and LS-DYNA) programs across a broad range of frequencies, earthquake shaking intensities, and sites ranging from stiff sand to hard rock, all with a focus on application to safety-related nuclear structures. Results show that the equivalent linear method is unable to reproduce the high frequency acceleration response, resulting in almost constant spectral accelerations in the short period range. Analysis using LS-DYNA occasionally results in some unrealistic high frequency acceleration ‘noise’, which can be removed by smoothing the piece-wise linear backbone curve. Analysis using DEEPSOIL results in abrupt variations in the peak strains of consecutive soil layers. These variations are found to be a consequence of the underlying hysteresis rules. There are differences between the site response predictions from equivalent linear and nonlinear programs, especially for large strains and higher frequencies, which are important for nuclear applications. The acceleration predictions from nonlinear programs are reasonably close for most cases, but the peak strain predictions can be significantly different despite using identical backbone curves. Variability in the predictions of different site response analysis programs is significant for large strains and at higher frequencies, underlining the need for the validation of these programs. Biaxial horizontal site response analyses are also performed for the stiff soil site using LS-DYNA. Results from these analyses show that the inclusion of the orthogonal component of the ground motion in site response analysis can significantly influence the acceleration response.