In this study, a method is proposed to activate the maximal in-sewer storage volume of a combined sewer system (CSS) with a limited number of flow regulators to reduce negative impacts of combined sewer overflows (CSO). Based on a detailed analysis of the CSS structure, it indicates suitable locations to install flow regulators. The method has been developed in the programming language R and tested on the Berlin’s biggest CSS. Flow regulators have been implemented in the CSS Infoworks model at the five most suitable locations found and tested for different rainfall conditions. It was found that significant additional in-sewer storage capacity can be activated (~50% of the already existing capacity) leading to CSO volume and pollutant load reductions up to 62% for a three-monthly rain event of 60 minutes duration.