A cable-stayed bridge was analyzed with actual earthquake records to investigate the effects of MSE. Arias intensities of recorded input excitations elaborated the variability of input excitations. Comparison of MSE and SE analyses disclosed the increase in engineering demands under MSE and clarified the contribution of anti-symmetric modes as well as some higher symmetric modes to induce the response amplifications. Estimates of impact factors indicated the detrimental effects of MSE on intermediate piers. Moreover, sensitivity analysis revealed the influence of MSE on edge piers too. Additional work is necessary to aid the current seismic design codes for MSE records selection and estimation of engineering demand parameters with limited uncertainties and enhanced confidence.