In this paper, we investigate the possibility of adopting the Once-Through (OT-MSF) design in place of the conventional brine recycle (BR-MSF) design for the future, large scale desalination plants. It was assumed here that efficient anti-scale chemicals would be available. Thus, a top brine temperature (TBT) of 120degreesC can be maintained without excessive scale formation. A comparison between the different MSF plant configurations was based on a plant capacity of 20 US-MGD, a gained output ratio of 10, a TBT of 120degreesC, a feed temperature and concentration of 35degreesC and 48000 ppm respectively. The main objective of the calculations is to predict the optimal design for a selected configuration where the total heat transfer area is minimal. The total number of stages was varied stepwise from 20-40 stages. A rigorous mathematical model has been used to solve the optimization problem taking into consideration the nonlinearity of the thermo-physical properties of seawater and steam. The Solver tool of Microsoft Excel was used to find out the optimal solutions. A comparison of the specific heat transfer areas (m(2)/kg/s) calculated for the different plant configurations having a total number of stages equal to 40, revealed that the same water capacity and the same gained output ratio can be obtained from a Long-Tube (LT)-MSF plant with about 40% reduction in heat transfer area relative to the conventional Cross-Tube (CT)-BR-MSF plant design. Nevertheless, when comparing the specific heat transfer areas obtained for the global optimal designs of the different configurations, having different numbers of stages, we find that the use of the OT designs is not likely to save more than 1% in heat transfer area relative to the conventional CT-BR-MSF configuration. These results say that the LT-OT design will be favorable only when the total number of stages is 40 or more. As expected, findings related to the specific chemical consumption were not in favor of the OT plants where the consumption ratio varies between 1.7 and 1.9 relative to the conventional CT-BR plant. This disadvantage penalizes the cost of water produced by MSF plants of the OT configurations due to the increased operating cost. The increase in operating costs has to be weighed against the saving in capital cost and lower power consumption due to the elimination of the recycle pump and the heat rejection section.