This paper aims at analyzing the effects of soil non-homogeneity on the dynamic behavior of piled structures. In order to fulfil this objective a procedure based on a substructuring model, which includes soil-structure interaction effects, is used to compute the dynamic response of slender and non-slender structures supported on several pile group configurations embedded in four different linear-elastic Gibson soil profiles. A numerical model based on the integral formulation of the elastodynamic problem and Green’s functions for the layered half space is used for the purpose of determining the foundation dynamic response in terms of impedances and kinematic interaction factors. The results obtained in terms of structural base shear force for each one of the variable-with-depth soil profiles are compared to those computed for an equivalent homogeneous soil. A significant influence of the soil profile on the structural harmonic response to seismic waves is observed in terms of maximum shear force at the base of the structure. The homogeneous assumption when modelling depth-varying soil profiles yields, in many cases, non-conservative results when predicting the structural dynamic behavior.