A systematic model for chemical oxygen demand (COD) removal using the ANAMMOX (Anaerobic AMMonium OXidation) process was provided based on an experimental design. At first, the experimental data was collected from a combined biological aerobic/anaerobic reactor. For modelling and optimization of COD removal, the main parameters were considered, such as COD loading, ammonium, pH, and temperature. From the models, the optimum conditions were determined as COD 97.5 mg/L, ammonium concentration equal to 28.75 mg-N/L, pH 7.72, and temperature 31.3°C. Finally, the analysis of the optimum conditions, performed by the response surface method, predicted COD removal efficiency of 81.07% at the optimum condition.