In order to reduce the formation of disinfection by-products (DBPs) during potabilization of water it is necessary to explore the potential of the source water and the applied treatment to generate these chemicals. This is actually more challenging in large drinking water networks that use different source waters to satisfy drinking water demand. In this regard, this work investigated the formation of DBPs in water matrices that are commonly supplied to the city of Barcelona and its metropolitan area. The regulated trihalomethanes and haloacetic acids were the most abundant DBP classes in these waters, followed by haloacetamides and haloacetonitriles or trihalogenated acetaldehydes (THALs). On the contrary, the formation potential of iodo-DBPs was minor. Mixing of drinking water treatment plant finished waters with desalinated water decreased the overall DBP formation potential of the water but resulted in the increased formation of brominated DBPs after long chlorine contact time. The formation of most DBPs was enhanced at high water temperatures (except for Br-THALs) and increasing residence times. Potential cytotoxicity and genotoxicity of the DBP mixtures were mainly attributed to the presence of nitrogen-containing DBPs and HAAs.