Assessment of potential seismic risk and losses in urban environments is necessary for several purposes ranging from risk mitigation to city and regional planning. It is well known that loss estimation should be performed within an interdisciplinary setting involving earth sciences and engineering. Field experience from recent events worldwide shows that the spatial variability of seismic damage is due to the combined effects of earthquake source properties, local site conditions and structural characteristics. In this study, a scenario-based multi-input damage estimation framework in an urban region was utilized for the Gaziantep city center (southeastern Turkey) that is located in a region of high seismic hazard with no large events in the instrumental era. Initially, a thorough geological and seismotectonic assessment of the area was performed followed by estimation of two critical scenario events with moment magnitude (Mw) of 6.5 and 6.6 on nearby active faults. Then, a regional velocity model was compiled from regressions of existing regional geotechnical and seismic data in terms of the VS30 parameter. As the next step, field surveys for the assessment and classification of buildings in the study area were performed followed by vulnerability analyses. As the last step, the mean damage ratios were computed at 198 neighborhoods within the city center. The results indicate not only a high hazard but also high risk in the Gaziantep area due to the combination of close proximity to the faults along with local site effects and building fragilities.