The aggregate loss to a portfolio of buildings given a seismic event is of interest to parties such as insurance companies, developers, political organizations and community planners. Regional level estimations tend to be more complex than site-specific assessments due to the correlation that exists between the performances of spatially distributed buildings within a single hazard. This paper presents a new reliability-based approach to quantify seismic risk for a portfolio of buildings, while incorporating this correlation. The proposed framework uses the First-Order Reliability Method (FORM) to evaluate a probability distribution of loss for a suite of spatially distributed buildings. It is applied to a San Francisco neighborhood building inventory to estimate the distribution of total repair cost given a scenario earthquake and prioritize cost-effective retrofit schemes in terms of reducing portfolio loss. The information provided by using the proposed method is expected to facilitate more efficient risk management and mitigation decision-making. (C) 2014 Elsevier Ltd. All rights reserved.