Abstract: The seismic failure mode of uniform damage refers to that the structure has a uniform damage and story drift along the height and develops a global energy dissipation mechanism, and it is an ideal and expected failure mode. A uniform damage-based seismic optimization design approach for RC frame structures considering the soil-structure interaction is proposed. By taking the uniformity of maximum inter-story drift ratio (IDR) as the design objective, the seismic optimization design approach was developed. Moreover, the optimization procedure accounted for the IDR distribution and component rotation demands. The component’s sectional reinforcements were selected as the design variables, and the material cost and the reinforcement ratio were considered as the design constraints. Based on the Beam on Nonlinear Winkler Foundation (BNWF) model, the numerical model of the RC frame structure considering soil-structure interaction was established. Two RC frame structures with 5 and 12 stories were employed as the prototype structures. The effects of convergence parameters on the convergence speed and stability were investigated. The transfer of story reinforcements in the optimization was studied. The change of component rotation and IDR distribution after the optimization was analyzed. The analytical results indicate that the developed approach can achieve a uniform IDR distribution and a smaller maximum IDR, thus improving the seismic performance.