Understanding the physical vulnerability of buildings and infrastructure to natural hazards is an essential step in risk assessment for large cities. We have interpreted high spatial resolution images, conducted field surveys, and utilized numerical simulations, in order to assess vulnerability across Arequipa, south Peru, close to the active El Misti volcano. The emphasis of this study was on flash floods and volcanic or non-volcanic hyperconcentrated flows, which recur on average every 3.5 years across the city. We utilized a geographic information system to embed vulnerability and hazard maps as a step to calculate risk for buildings and bridges along the Río Chili valley and two tributaries. A survey of ~1,000 buildings from 46 city blocks, different in age, construction materials, and land usage, provided architectural and structural characteristics. A similar survey of twenty bridges across the three valleys was based on structural, hydraulic, and strategic parameters. Interpretation of high spatial resolution (HSR) satellite images, which allows for quick identification of approximately 69 % of the structural building types, effectively supplemented field data collection. Mapping vulnerability has led us to pinpoint strategic areas in case of future destructive floods or flows. Calculated vulnerability is high if we examine structural criteria alone. We further consider physical setting with the most vulnerable city blocks located on the lowermost terraces, perpendicular or oblique to the flow path. Statistical analysis conducted on 3,015 city blocks, considering nine criteria identified from HSR images, indicated that building-type heterogeneity and the shape of the city blocks, along with building and street network density, are the most discriminant parameters for assessing vulnerability.