Treatment of domestic wastewater using microbial fuel cells (MFCs) will require reactors with multiple electrodes, but this presents unique challenges under continuous flow conditions due to large changes in the chemical oxygen demand (COD) concentration within the reactor. Domestic wastewater treatment was examined using a single-chamber MFC (130 mL) with multiple graphite fiber brush anodes wired together and a single air cathode (cathode specific area of 27 m2/m3). In fed-batch operation, where the COD concentration was spatially uniform in the reactor but changed over time, the maximum current density was 148 ± 8 mA/m2 (1,000 Ω), the maximum power density was 120 mW/m2, and the overall COD removal was >90 %. However, in continuous flow operation (8 h hydraulic retention time, HRT), there was a 57 % change in the COD concentration across the reactor (influent versus effluent) and the current density was only 20 ± 13 mA/m2. Two approaches were used to increase performance under continuous flow conditions. First, the anodes were separately wired to the cathode, which increased the current density to 55 ± 15 mA/m2. Second, two MFCs were hydraulically connected in series (each with half the original HRT) to avoid large changes in COD among the anodes in the same reactor. The second approach improved current density to 73 ± 13 mA/m2. These results show that current generation from wastewaters in MFCs with multiple anodes, under continuous flow conditions, can be improved using multiple reactors in series, as this minimizes changes in COD in each reactor. © 2012 Springer-Verlag Berlin Heidelberg.