Water loss is an issue that affect Water Distribution Systems (WDSs) very often, especially when aged and high pressure occurs. Pressure reduction valves (PRVs) can be used as devices to reduce as much as possible the water losses within the network. Indeed, for a given number of PRVs, the daily volume of water lost from the network can be reduced minimizing the pressure through a proper choice of valve positions as well as their settings. In this paper, a methodology for the optimal number, positioning and setting of PRVs is presented. In the proposed methodology, a genetic algorithm is coupled with a physical modelling of leakage from joints and a simplified and yet realistic hydraulic simulation of the WDS. The proposed methodology is demonstrated using two WDSs examples. Comparisons with a more extreme and complicated hydraulic modelling, already proposed by authors in previous work, are also performed in the first case study in order to validate the proposed methodology. These comparisons demonstrate that the methodology proposed in this work performs fairly well when compared to similar approach that uses a more sophisticated hydraulic model. As a consequence, it revealed to be a good tool for the optimal positioning and sizing of PRVs within WDS aimed at reducing the background leakages even when the WDS is characterized by complex geometry and topology.