Multi-stage flash (MSF) and reverse osmosis (RO) are the most common techniques for seawater desalination. A significant difference between these methodologies consists of their different energy requirements, i.e., thermal energy for MSF and mechanical energy for RO plants. The presence of both desalination systems (MSF and RO) appears to be suitable for cogeneration plants. The reject heat from the power cycle can feed an MSF section, while some power feeds the RO section and the MSF auxiliary equipment; the rest is sold to the grid. A criterion for the optimal design of such tri-functional cogeneration plants is proposed, based on exergo-economics and on profit maximization. In particular, in this work the analytical model is presented by examining the required data, expressing the physical and cost balances and furnishing a comprehensive definition of the objective function. The proposed model is flexible and suitable for comparative applications in all Mediterranean countries.