Specific ion effects on the aggregation behavior of a reference aquatic natural organic matter (NOM), Suwannee River NOM (SRNOM), were investigated using kinetic, titration, calorimetric, and surface tension methods. Monovalent cations induced structural compacting of SRNOM, but not its aggregation. Their ability to induce structural compacting follows the order: Cs+ > Rb+ > K+ > Na+ > Li+. Divalent cations except Mg2+ can readily induce SRNOM aggregation. Their critical coagulation concentrations (CCC) follow the order: CCCSr > CCCCa > CCCBa. Electrokinetic, titration, and calorimetric data suggest that monovalent cations have weak interactions with SRNOM, while divalent cations strongly interact with SRNOM. Overall, the cation specificity in aggregation is determined by cation-NOM interactions and their ability to modulate surface tension. Specific ion effects of monovalent cations correlate to their hydration free energy, while that of divalent cations correlate to the ratio of the hydration entropy of cation to the enthalpy change of cation-NOM interactions. The cation specificity is consistent with the extended Derjaguin-Landau-Verwey-Overbeek theory, and the intermolecular interaction energy is dominated by the Lewis acid-base interactions. Our results suggest that specific cations should be targeted to predict or manipulate intermolecular interactions of aquatic NOM in natural and engineered settings. (C) 2019 Elsevier Inc. All rights reserved.