Wastewater from the milk industry usually undergoes activated sludge ahead of refining treatments, final discharge or reuse. To identify the most effective bioreactor hydraulic regime for the secondary treatment of wastewater resulting from the milk industry in an activated sludge system, two lab-scale activated sludge systems characterized by a different configuration and fluid dynamics (i.e., a compartmentalized activated sludge (CAS) with plug flow regime and a complete mixed activated sludge (AS)) were operated in parallel, inoculated with the same microbial consortium and fed with identical streams of a stimulated dairy wastewater. The effect of three process and operational variables--influent chemical oxygen demand (COD) concentration, sludge recycle ratio (R) and hydraulic retention time (HRT)--on the performance of the two systems were investigated. Experiments were conducted based on a central composite face-centered design (CCFD) and analyzed using response surface methodology (RSM). The region of exploration for treatment of the synthetic wastewater was taken as the area enclosed by the CODin (200, 1,000 mg/l), R (1, 5), and HRT (2, 5 h) boundaries. To evaluate the process, three parameters, COD removal efficiency (E), specific substrate utilization rate (U), and sludge volume index (SVI), were measured and calculated over the course of the experiments as the process responses. The change of the flow regime from complete-mix to plug flow resulted in considerable improvements in the COD removal efficiency of milk wastewater and sludge settling properties. SVI levels for CAS system (30-58 ml/g) were considerably smaller that for the AS system (50-145 ml/g). In addition, the biomass production yield could be reduced by about 10% compared to the AS system. The results indicated that for the wastewater, the design HRT of a CAS reactor could be shortened to 2-4 h.