Using the probabilistic and holistic approach of the CAPRA platform to assess seismic risk at the urban level, the decision-making process to reduce different dimensions of vulnerability and increase local resilience from an integral and inter-institutional perspective is described. The risk assessment methodology has been developed and applied to define real multisectoral actions, such as prioritizing the structural reinforcement of essential buildings, insuring public and private assets using cross-subsidies to cover the low-income households, making the intervention of relevant lifelines components, reviewing land-use planning, implementing automated and online shakemaps and post-earthquake damage evaluation systems, and making the generation of emergency response scenarios. This paper describes the holistic approach used for seismic risk assessment considering the direct physical effects and their impact using indicators of social fragility and lack of resilience as factors of amplification or aggravation and as socio-economic risk drivers in the different territorial units at urban level. The process of evaluation and decision-making is illustrated in the city of Manizales, Colombia; in which the effectiveness of risk management based on a comprehensive risk assessment has been demonstrated and where the assessment methodology not only reveals risk but also guides, with its approach, the actions to be taken.