This study proposes an optimal study of reverse osmosis (RO) seawater desalination system based on the split partial second pass (SPSP) design in order to fully utilize better quality and higher flux for the permeate at the front of the pressure vessel (PV). Differential equations in the membrane transport model are solved by finite difference method, which considers the longitudinal variation of the superficial velocity, the pressure and the salinity inside the PV. Superstructure optimization is adopted to determine optimal flow structure, appropriate membrane type, and operation conditions. Firstly, single product RO system has been optimized, cost breakdown and sensitive analysis reveal that membrane with large active area and high salt rejection is favored for SPSP. System recovery, pressure, and split ratio for the permeate of pass 1 should be adjusted with time in order to decrease total annualized cost. Secondly, multiple product RO system has been studied. Three-pass RO configuration with permeate reprocessed and brine recycled is favored for the system with two permeate products. The optimal RO configuration with three permeate products is influenced by flow rates and required permeate concentrations. In general, SPSP could provide lower cost, lower energy consumption, and smaller system size than normal design. (C) 2015 Elsevier B.V. All rights reserved.