Significant and rapid developments have taken place recently in the multi-effect thermal vapor compression (ME-TVC) desalination system of SIDEM Company, particularly in enlarging the unit capacity. The new trend of combining ME-TVC with conventional multi-effect has allowed this unit capacity to increase from two to eight million imperial gallons per day (MIGD) in the last decade. This considerable increase in capacity, poses a real competition to the multi stage flash system (MSF) as a large-scale production plant with lower operation temperatures. A steady state mathematical model of the ME-TVC desalination system is developed in this paper using Engineering Equations Solver (EES) to evaluate the model system performance. The model validity is examined against three commercial ME-TVC units which showed good results. The main improvements in the performance during the past ten years are also outlined and discussed. Another purpose of this paper is to determine the optimum operating and design conditions of the ME-TVC desalination system through mathematical modeling optimization. A MATLAB algorithm Solution is developed and used to solve model equations. where a different number of effects were tested to maximize the gain ratio using (1) Smart Exhaustive Search Method and (2) Sequential Quadratic Programming. Results showed that the maximum gain ratio varied between 8.5 and 18.5 for 4 and 12 effects with the optimal top brine temperature ranging between 55.8 and 67.5 degrees C and a reasonable specific heat transfer area. The optimal ranges of compression and entrainment ratios are between 1.81 to 3.68 and 0.73 to 1.65 respectively. The optimal results of 4-effect TVC unit are also compared with three commercial 4-effect units having almost the same input, which showed that further improvement in the distillate output production, compression and entrainment ratio can be achieved by combining the ME-TVC system with conventional multi-effect unit. (C) 2009 Elsevier B.V. All rights reserved.