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This study reports an investigation of the concept, application and performance of a novel bioelectrochemical nitritation-anammox microbial desalination cell (MDC) for resource-efficient wastewater treatment and desalination. Two configurations of anammox MDCs (anaerobic-anammox cathode MDC (AnA_moxMDC) and nitration-anammox cathode MDC (NiA_moxMDC)) were compared with an air cathode MDC (CMDC), operated in fed-batch mode. Results from this study showed that the maximum power density produced by NiA_moxMDC (1,007 mW/m³) was higher than that of AnA_moxMDC (444 mW/m³) and CMDC (952 mW/m³). More than 92% of ammonium-nitrogen (NH₄⁺-N) removal was achieved in NiA_moxMDC, significantly higher than AnA_moxMDC (84%) and CMDC (77%). The NiA_moxMDC performed better than CMDC and AnA_moxMDC in terms of power density, COD removal and salt removal in desalination chamber. In addition, cyclic voltammetry analysis of anammox cathode showed a redox peak centered at −140 mV Vs Ag/AgCl confirming the catalytic activity of anammox bacteria towards the electron transfer process. Further, net energy balance of the NiA_moxMDC was the highest (NiA_moxMDC-0.022 kWh/m³>CMDC-0.019 kWh/m³>AnA_moxMDC-0.021 kWh/m³) among the three configurations. This study demonstrated, for the first time, a N-E-W synergy for resource-efficient wastewater treatment using nitritation-anammox process.