The growth in high-rise building construction has increased the need for hybrid reinforced concrete and steel structural systems. Columns in buildings are the most important elements because of their seismic resistance. Reinforced concrete (RC) columns and steel columns were used herein to form hybrid structural systems combining their distinct advantages. Eleven 3D building models subjected to earthquake excitation with reinforced concrete beams and slabs of 12 floors in height and with different distributions of mixed columns were analyzed by the SAP2000 software in order to investigate the most suitable distributions of a combination of reinforced concrete and steel columns. Top displacements and accelerations, base normal forces, base shear forces, and base bending moments were computed to evaluate the selected hybrid structural systems. The findings are helpful in evaluating the efficiency of the examined hybrid high-rise buildings in resisting earthquakes.