In this study, we present an investigation into the seismic vulnerability assessment of medium-rise reinforced concrete structures featuring vertical geometric Irregularity (setback). We considered the effects of the percentage and location of the setback along the height of the building, as well as the impact of changing site classes. Additionally, we incorporated the effects of soil-structure interaction into the nonlinear response of the building. In the first part, we investigated the influence of the aforementioned parameters on the seismic response of a structure through nonlinear static analyses. We analyzed the capacity curves and the development of plastic hinges in the structural elements. In the second part, we analyzed the seismic fragility of building frames using a probabilistic study approach. We developed fragility curves to assess the vulnerability of the structures.In conclusion, the obtained results highlight the fundamental importance of considering structural Irregularities as well as the impact of different site classes on the seismic vulnerability of Buildings.