The aim of this study was to compare the efficiency of different disinfectants applicable to Legionella control in domestic water systems. A domestic water supply simulation unit that allowed simulation of real-world conditions was developed for this purpose. The system, consisting of seven identical rigs, was used to compare treatment efficiency under equivalent conditions of system design, materials, hydraulics, water quality, temperature and initial contamination. During the study, each of six loops received continuous application of one of the following disinfectants: chlorine, electro-chlorination, chlorine dioxide, monochloramine, ozone, or copper/silver. The seventh loop was used as a control and remained untreated. Performance evaluation of these disinfectants was based on their ability to reduce not only Legionella, but also protozoa and biofilms, which contribute to the establishment and dissemination of these bacteria in water systems, and their resistance to treatments. Regarding these criteria, chlorine dioxide and chlorine (as bleach or obtained by electro-chlorination) were the most effective treatments in this study. However, in comparison with chlorine, chlorine dioxide showed a longer residual activity in the system, which constituted an advantage in the perspective of an application to extensive pipework systems.