Fouling potentials caused by particulate matters are generally evaluated by fouling index, such as SDI and MFI, widely used in RO membrane practices. However, these fouling indices failed to predict the effect of nanocolloidal sizes on flux decline, implying that colloidal fouling is too complex to be analyzed by simple fouling index. Thus, in this study, nano-colloidal fouling mechanism in seawater reverse osmosis (SWRO) desalination was fundamentally investigated by employing new approach. Specifically, the specific cake resistance of colloidal foulants was first determined by a novel method, cake resistance simulator-modified fouling index nanofiltration (MFI-NFCRS), which was conducted under operating pressure and solute environment similar to those of real SWRO desalination. Then colloidal deposition and resulting cake-enhanced osmotic pressure (CEOP) were quantitatively assessed by fitting RO experimental data to the calculations from the CEOP model. The results clearly demonstrated that the flux decline caused colloidal deposition in the SWRO process depended greatly on the CEOP. The newly developed methodology including MFI-NFCRS is expected to contribute significantly to better understand nano-colloidal fouling mechanisms and to accurately predict their fouling potentials in the SWRO desalination. (C) 2014 Elsevier B.V. All rights reserved.