Uncertainties involved in the characterization and seismic response of soil-foundation-structure systems along with the inherent randomness of the earthquake ground motion result in very complex (and often controversial) effects of soil-foundation-structure interaction (SFSI) on the seismic response of structures. Conventionally, SFSI effects have been considered beneficial (reducing the structural response), however, recent evidence from strong earthquakes has highlighted the possibility of detrimental effects or increase in the structural response due to SFSI. This paper investigates the effects of SFSI on seismic response of structures through a robust Monte Carlo simulation using a wide range of realistic SFS systems and earthquake input motions in time-history analyses. The results from a total of 1.36 million analyses are used to rigorously quantify the SFSI effects on structural distortion and total horizontal displacement of the structure, and to identify conditions (system properties and earthquake motion characteristics) under which SFSI increases the structural response.