Because changes in the structure's occupancy significantly affect the mass distribution and the structure's behavior, changing mass distribution might make the building more irregular and vulnerable to seismic ground motions. Many researchers tried to evaluate their seismic vulnerability. Most previous studies used simplified structural representations such as two-dimensional models that could not represent accurate seismic behavior from the coupling between lateral and torsional responses. For space structures with high irregularity, more realistic representations such as three-dimensional models are needed for the proper seismic assessment. To handle the computational challenge in deriving fragility curves, this research utilized a new structural reliability method that incorporates structural analysis and reliability analysis to efficiently and accurately calculate the failure probability with the first-order reliability method (FORM). This study investigates the seismic vulnerability of space-reinforced concrete frame structures with varying vertical irregularities. More representative seismic fragility curves are derived with their three-dimensional analytical models. The significant effect of the structure's vertical irregularity on seismic vulnerability is highlighted.