The mathematical model for the performance prediction of a multi-effect desalination system with thermal vapor compression (MED-TVC) and a reverse osmosis (RO), was presented. To develop the mathematical model, the energy and concentration conservation laws were applied by considering the Boiling Point Elevation and various thermodynamic losses. This analysis led to the determination of the thermodynamic properties at different points and the Gain Output Ratio value. The exergy analysis of a sea water RO desalination plant was performed and its performance was investigated. A computational model based on the diffusion and convection transport mechanisms as well as the concentration polarization concept, was developed to predict the performance of the RO membrane. Then, the hybrid MED-RO desalination system was studied, the irreversibility analysis was performed and the exergy destruction (considering chemical and physical exergy), exergetic efficiency and system performance were assessed. To obtain the optimum point of the system, the multi-objective optimization with the genetic algorithm tool was used. The determination of the best tradeoff between the exergetic efficiencies of MED and RO, was the final goal of this optimization. The optimum design led-to the selection of a MED-RO hybrid system with the highest exergetic efficiency. (C) 2016 Elsevier B.V. All rights reserved.