A larger (6.1 L) MFC stack made in a scalable configuration was constructed with four anode modules and three (two-sided) cathode modules, and tested at a wastewater treatment plant for performance in terms of chemical oxygen demand (COD) removal and power generation. Domestic wastewater was fed either in parallel (raw wastewater to each individual anode module) or series (sequentially through the chambers), with the flow direction either alternated every one or two days or kept fixed in a single direction over time. The largest impact on performance was the wastewater COD concentration, which greatly impacted power production, but did not affect the percentage of COD removal. With higher COD concentrations (∼500 mg L−1) and alternating flow conditions, power generation was primarily limited by the cathode specific area. In alternating flow operation, anode modules connected to two cathodes produced an average maximum power density of 6.0 ± 0.4 W m−3, which was 1.9 ± 0.2 times that obtained for anodes connected to a single cathode. In fixed flow operation, a large subsequent decrease in COD influent concentration greatly reduced power production independent of reactor operation in parallel or serial flow modes. Anode modules connected to two cathodes did not consistently produce more power than the anodes connected to a single cathode, indicating power production became limited by restricted anode performance at low CODs. Cyclic voltammetry and electrochemical impedance spectroscopy data supported restricted anode performance with low COD. These results demonstrate that maintaining power production of MFC stack requires higher influent and effluent COD concentrations. However, overall performance of the MFC in terms of COD removal was not affected by operational modes.