This work addresses the comparison of seawater desalination by the RO-PRO hybrid system with open-loop and closed-loop configurations regarding normalized specific energy consumption (NSEC) using a model-based optimization approach. The NSECs in both configurations are minimized by solving a constrained nonlinear optimization model so that the comparison is addressed based on their best conditions. The underlying impacts of membrane area, pretreatment energy of feed water, feed water concentration and internal concentration polarization on system performances are systemically investigated. It is shown that the optimization program gives priority to the closed-loop configuration due to its advantages in energy-saving and cost reduction at an adequate membrane area (gamma(tot) >= 1.0) and low water recovery (Y <= 0.5). It highlights the significance of an essential prerequisite gamma(tot,min) > pi Y-0/(sigma(Delta pi(PRO)) over bar) for the operation of a closed-loop configuration. Nevertheless, the analysis of internal concentration polarization effect further indicates that the closed-loop configuration may be vulnerable to the variation of operating and feed conditions and the degradation of membrane in practice.