Reverse electrodialysis harvests energy from salinity gradients establishing a renewable energy source. High energy efficiencies are fundamental to up-scale the process and to minimize feedwater pre-treatment and pumping costs. The present work investigates electrode segmentation to strategically optimize the output power density and energy efficiency. Electrode segmentation allows the current density to be tuned per electrode segment. Segmentation experiments were performed with a dedicated electrode configuration in a cross-flow stack using a wide range of residence times. Moreover, an experimentally validated model was extended and used to further compare single and segmented electrode configurations. While operating the electrode segments, the highest efficiencies were obtained when considering the overall power, i.e. not maximized by segment. Results show that at a given net power density (0.92 W·m−2), electrode segmentation increases the net energy efficiency from 17% to 25%, which is a relative increase of 43%. Plus, at 40% net energy efficiency the net power output for a segmented electrode configuration (0.67 W·m−2) is 39% higher than in a single electrode configuration. Higher power density reduces capital investment and higher energy efficiency reduces operating costs. Electrode segmentation increases these parameters compared to a single electrode and can be potentially applied for up-scaling.