Regional seismic loss assessment of buildings requires ground‐motion intensity measure (IM) maps. In this article, a new method to estimate the seismic structural losses of urban regions is developed. Unlike the IMs commonly predicted by ground‐motion prediction equations (GMPEs), this method focuses on generating IM maps based on ground‐motion simulation, site‐response analysis, and geostatistical approaches. The seismic structural loss estimates are conducted for the building inventory of Singapore under a deterministic Sumatran earthquake scenario with moment magnitude () 7.7. Based on the collected soil profiles in Singapore, site‐response analyses are performed using the simulated bedrock motions. Kriging techniques are utilized to produce surface ground‐motion intensity maps. The structural losses are then estimated using the simulated intensity maps, and the capacity and fragility curves provided in Hazards U.S. Multi‐Hazard (HAZUS‐MH). The estimated structural losses by this simulation‐based method are compared systematically with those obtained by the GMPE‐based loss estimation method. The influence of the spatial variability of IMs on seismic loss estimates is also discussed. The simulation‐based approach can account better for small‐scale variability of site conditions. It is applicable to urban regions where adequate attention should be paid to site effects.