In this study, various foulants are tested with the conventional fouling indexes such as silt density index (SDI) and modified fouling index (MFI) under high TDS conditions to evaluate the practical appliance of these indexes for RO desalination. A new approach for developing a more realistic fouling index is investigated based on flow field-flow fraction (Fl-FFF) analysis. The results showed that the SDI and MFI for the feed waters containing the particulate foulants larger than the pore size of the membranes used in SDI and MFI measurements were not significantly affected by the feed water salinity. This is due to the fact I hat the main fouling mechanism is the deposition of particles on the membrane surface and, hence, the cake filtration controls the permeate flux. In case of the particles as well as organics smaller than the pore size of the membranes, the SDI and MFI failed to accurately predict the fouling potential of feed waters with high salinity. In addition, the characteristics of membrane (i.e., hydrophobicity) also played an important role in determining membrane performance. Based on the results from Fl-FFF analyses, it was demonstrated that both qualitative and quantitative assessments of fouling potential of feed waters with different foulants and TDS conditions were possible.