The effect of soil-structure interaction on a single-storey, two-bay space frame resting on a pile group embedded in the cohesive soil (clay) with flexible cap is examined in this paper. For this purpose, a more rational approach is resorted to using the finite element analysis with realistic assumptions. Initially, a 3-D FEA is carried out independently for the frame on the premise of fixed column bases in which members of the superstructure are discretized using the 20-node isoparametric continuum elements. Later, a model is worked out separately for the pile foundation, by using the beam elements, plate elements and spring elements to model the pile, pile cap and soil, respectively. The stiffness obtained for the foundation is used in the interaction analysis of the frame to quantify the effect of soil-structure interaction on the response of the superstructure. In the parametric study using the substructure approach (uncoupled analysis), the effects of pile spacing, pile configuration, and pile diameter of the pile group on the response of superstructure are evaluated. The responses of the superstructure considered include the displacement at top of the frame and moments in the columns. The effect of soil-structure interaction is found to be quite significant for the type of foundation considered in the study. Fair agreement is observed between the results obtained herein using the simplified models for the pile foundation and those existing in the literature based on a complete three dimensional analysis of the building frame - pile foundation - soil system.