Abstract: This paper revisited the effect of soil–structure interaction (SSI) on the nonlinear response of multistory buildings with a probabilistic approach. In particular, this study showed that the magnitude of SSI effects on the strength demand of a multiple-degree-of-freedom (MDOF) system stems from the effect of soil–structure interaction on the corresponding equivalent single-degree-of-freedom (eSDOF) system. This seems to negate several past studies on flexible-base MDOF systems. In fact, such studies did not quantify the split between contributions of SSI effects to the corresponding eSDOF system and to those unique aspects of MDOF systems that cannot be represented by the eSDOF system. Doing so in the present paper showed that the effect of SSI on the inelastic response of MDOF systems can be well predicted based on the knowledge of the soil–structure interaction effect on the response of SDOF systems, i.e., the share of MDOF aspects of the system in this effect is insignificant. Based on this finding, a procedure is proposed to determine the strength demand of a flexible-base shear building given a target ductility demand.