Laboratory experiments and model calculations were performed to elucidate the fundamental interactions that control organic fouling in reverse osmosis (RO) processes. Bovine serum albumin and alginic acid were selected as model aquatic organic macromolecules (organic foulants). An extended Derjaguin-Landau-Verwey-Overbeek (DLVO) characterization analysis was used to elucidate mechanisms of organic matter fouling on a commercial, polyamide composite RO membrane. Surface tension parameters derived from contact angle analyses are used to demonstrate that the apparent thermodynamic stability of macromolecules determines and adhesive free energy between membranes and macromolecules explained the observed differences in flux decline. Further, foulant-membrane and foulant-foulant interfacial forces helped explain why hydrophilic macromolecules formed polarization layers causing minimal flux decline, while hydrophobic macromolecules formed gel (or cake) layers that led to severe flux decline.