This paper presents the theoretical basis and the main results obtained during the development and full-scale experimental validation of the new supervisory control strategy designed for the Galindo-Bilbao wastewater treatment plant (WWTP). The different phases of the project have been carried out over the last 8 years, combining model simulations, pilot-plant experimentation and full-scale validation. The final control strategy combines three complementary control loops to optimise the nitrogen removal in pre-denitrifying activated sludge plants. The first controller was designed to maintain the average concentration of the ammonia in the effluent via the automatic selection of the most appropriate DO set point in the aerobic reactors. The second control loop optimises the use of the denitrification potential and finally, the third control loop maintains the selected amount of biomass in the biological reactors by automatic manipulation of the wastage rate. Mobile-averaged windows have been implemented to incorporate commonly used averaged values in the control objectives. The performance of the controllers has been successfully assessed through the full-scale experimental validation in one of the lines of the WWTP.