Membrane-based processes and thermal desalination plants are two alternatives to overcome the problem of fresh water supply by means of seawater desalination. In this work the combination of two types of desalination technologies, a reverse osmosis network (RON) and a forward-feed multi-effect distillation (FF-MED), in a hybrid plant is considered as a structural optimization problem. Deterministic mixed-integer non-linear programming techniques (MINLP) are used to rigorously optimize operational parameters and process structure simultaneously. A generalized superstructure for the hybrid desalination plant is constructed and conceptual design considerations are used to reduce its complexity. A mathematical model for the whole plant and an economical objective function are provided. The resulting model is highly nonlinear and non-convex. A stepwise optimization strategy is proposed, including a specialized initialization scheme to robustly compute good initial solutions with a minimum of user interaction. Results for various specifications illustrate the application of the proposed optimization model. The performance of the suggested method is compared to that obtained with the global solver BARON. (C) 2012 Elsevier B.V. All rights reserved.