This paper presents the comparison of four control strategies for the A²/O WWTP configuration for simultaneous C, N and P removal. The control strategies: (i) external COD-P control; (ii) external recycle flow-P control; (iii) nitrate control in the last anoxic reactor; (iv) ammonia control in the last aerobic reactor, were combined with other common control loops to build different control structures and were simulated in Matlab/Simulink under different influent conditions. A systematic approach was conducted with all the strategies to assess their potential effectiveness, according to the following steps: theoretical design, setpoint optimization and, finally, a detailed comparison of the control results against a reference operation and an optimized reference scenario. The optimization of the reference operation presented a 7% reduction of the total operational cost. The simulation results showed that some control strategies further reduced 3-7.5% the WWTP operational costs while the effluent quality is greatly improved.