This paper presents a novel mathematical formulation for modeling-based optimization of the multiple effect distillation (MED) water desalination process using thermal vapor compression (TVC). The presented model is based on a mass flowrate decoupling concept where flowrates of salt and water in the process are separately considered to allow for the development of a linear programming (LP) optimization formulation while accounting for process heat and mass balances. The system models include stream physical properties that are dependent on temperature, salinity, thermodynamic losses and other properties that are influenced by changes in system pressure such as brine and distillate flashing. The overall modeling approach was used to perform a thermo-economic analysis of the process as well as to identify novel flow routing options for boiler feed water return and de-superheating water sources. A sensitivity analysis was performed to evaluate the effects of various system parameters such as motive steam supply pressure, heating costs, seawater salinity and number of operating effects on the thermo-economically optimal design. (C) 2015 Elsevier B.V. All rights reserved.