Because significant damages to structures having structural irregularity in their plans were repeatedly observed during many past earthquakes, there have been great research efforts to evaluate their seismic vulnerability. Although most of the previous studies used simplified structural representations such as one-dimensional or two-dimensional models in the fragility analysis of plan-irregular structures, simple analytical models could not represent true seismic behavior from the complicated nonlinear coupling between lateral and torsional responses as the degree of irregularity increased. For space structures with high irregularity, more realistic representations such as threedimensional models are needed for proper seismic assessment. However, the use of computationally expensive models is not practically feasible with existing approaches of fragility analysis. Thus, in this study, a different approach is adopted that can produce vulnerability curves efficiently, even with a three-dimensional model. In this approach, an integrated computational framework is established that combines reliability analysis and structural analysis. This enables evaluation of the limit-state faction without constructing its explicit formula, and the failure probability is calculated with the first-order reliability method (FORM) to deal with the computational challenge. Under the integrated framework, this study investigates the seismic vulnerability of space reinforced concrete frame structures with varying plan irregularity. Material uncertainty is considered, and more representative seismic fragility curves are derived with their three-dimensional analytical models. The effectiveness of the adopted approach is discussed, and the significant effect of structural irregularity on seismic vulnerability is highlighted.