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Reverse electrodialysis (SGP-RE or RED) represents a viable technology for the conversion of the salinity gradient power into electric power. A comprehensive model is proposed for the RED process using sea or brackish water and concentrated brine as feed solutions. The goals were (i) reliably describing the physical phenomena involved in the process and (ii) providing information for optimal equipment design. For such purposes, the model has been developed at two different scales of description: a lower scale for the repeating unit of the system (cell pair), and a higher scale for the entire equipment (stack). The model was implemented in a process simulator, validated against original experimental information and then used to investigate the influence of the main operating factors and on power output. Feed solutions of different salinities were also tested. A good matching was found between predictions and experiments for a wide range of inlet concentrations, flow rates and feed temperatures. Optimal feed conditions, for the adopted system geometry and membranes, have been found employing brackish water (0.08–0.1 M NaCl) as dilute and brine (4.5–5 M NaCl) as concentrate to generate the highest power density at 40 °C temperature. The model can be used to explore the full potential of the RED technology, especially for any investigation regarding the future scale-up of the process.