Pressure retarded osmosis (PRO) operated with active layer facing feed solution (AL-FS), in contrary to typical PRO membrane orientation (active layer facing draw solution, AL-DS), has a strong potential for sustainable power generation from salinity gradient energy with low membrane fouling. The feasibility of PRO in AL-FS mode was first examined by verifying less membrane deformation and insignificant shadow effect under pressurized PRO operation. The simulation of such PRO process showed that its low power density due to internal concentration polarization could be improved through reducing structural parameter of the support layer. Fouling experiments using synthetic wastewater clearly demonstrated that severe fouling observed with PRO operation at AL-DS was greatly reduced by switching PRO membrane orientation to AL-FS. Lastly, specific energy consumption of a PRO-RO hybrid process was assessed to be favorable in view of both power density and membrane fouling, suggesting that economically feasible power generation as well as effective water treatment can be achieved by operating PRO in the AL-FS orientation.