The fragility curves of space frames with multi-column loss are constructed in this research. A nine-story steel frame building having different column-loss scenarios is investigated. The loss of columns on the different stories, interior columns and exterior columns, with and without bracing is conducted with a rigorous time history analysis. The corresponding fragility curves of various column-loss scenarios are achieved with the maximum likelihood method. The fragility curves can be implemented to hazard reduction planning in the existing and new construction buildings for safety evaluation.