Seismic-resistant design incorporates measures to ensure that structures perform adequately under specific limit states, focusing on seismic forces derived from both the equivalent static and spectral modal methods. This study examined buildings on slopes in densely built urban areas, a common scenario in Latin American cities with high seismic risks. The adjustment of high-rise buildings to sloping terrains induces structural asymmetry, leading to plan and elevation irregularities that significantly impact their seismic response. This paper explores the asymmetry in medium-height reinforced concrete frame buildings on variable inclines (0°, 15°, 30°, and 45°) and its effect on their nonlinear response, assessed via displacements, rotations, and damage. Synthetic accelerograms matched with Chile’s high seismic hazard design spectrum, scaled for different performance states and seismic records from the Chilean subduction zone, were applied. The findings highlight structural asymmetry’s role in influencing nonlinear response parameters such as ductility, transient interstory drifts, and roof rotations, and uncover element demand distributions surpassing conventional analysis and in earthquake-resistant design expectations.