BioWin simulation model has been applied to two different anaerobic/aerobic systems. The first system was an anaerobic fluidized bed coupled with an up-flow anaerobic sludge blanket (UASB) reactor followed by a hybrid moving bed biofilm reactor (AFB-UASB/HMBBR). The second system was classical UASB followed by an activated sludge process (UASB/ASP). The model has been validated against the experimental results obtained from pilot plant reactors which are used to treat domestic wastewater at different hydraulic retention times (HRTs). The BioWin model showed a good representation of the measured data for the chemical oxygen demand (COD) for the two simulated systems. On the other hand, the applied model could give an approximate prediction for the removal ratio of the overall treatment process, including all measured parameters (biochemical oxygen demand (BOD), total suspended solids (TSS)) except for the ammonia removal ratio. Two pilot plants consisting of a combined AFB-UASB/HMBBR and UASB/ASP were tested for treating domestic wastewater. The investigated systems were operated for 116 d at a retention time of 4.5, 2.25 and finally at 1.5 h. The efficiency of the anaerobic stage in terms of COD ranged from 40% to 45%, while it was 40%–50% for BOD and 40%–43% for TSS. The overall removal efficiencies for the COD, BOD, and TSS in the system were 89%–93%, 90%–93%, and 91%–92% respectively. The experimental results of the present study indicated that the integrated AFB-UASB/HMBBR system that is applied to treat domestic wastewater is effective in the removal of COD, BOD as well as TSS fractions even at low HRT of 1.5 h. Also, the system shows high stability and performance recovery against operational problems.