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The automatic preservation of the indoor air quality (IAQ) is an important task of the intelligent building design in order to ensure the health and safety of the occupants. The IAQ, however, is often compromised by various airborne contaminants that penetrate the indoor environment as a result of accidents or planned attacks. In this paper, we provide the detailed analysis, implementation, and evaluation of a distributed methodology for detecting and isolating multiple contaminant events in large-scale buildings. Specifically, we consider the building as a collection of interconnected subsystems, and we design a contaminant event monitoring software agent for each subsystem. Each monitoring agent aims to detect the contaminant and isolate the zone where the contaminant source is located, while it is allowed to exchange information with its neighboring agents. For configuring the subsystems, we implement both exact and heuristic partitioning solutions. A main contribution of this paper is the investigation of the impact of the partitioning solution on the performance of the distributed contaminant detection and isolation (CDI) scheme with respect to the detectability and isolability of the contaminant sources. The performance of the proposed distributed CDI methodology is demonstrated using the models of real building case studies created on CONTAM.11CONTAM is a multizone simulation program developed by the U.S. National Institute of Standards and Technology. 26 6 1925 1941