Sulfamethoxazole (SMZ) adsorption by a series of amine-modified polystyrene–divinylbenzene resins (PSA/B/C/D) was investigated. All resins showed a similar pH dependent adsorption of SMZ but their capacities were linearly related with the contents of primary amines (NH₂) rather than secondary amines (NH). Mechanisms of SMZ adsorption by PSA (highest NH₂ content) were discussed as an example. Due to comparable pK_a, H-bonding interactions of NH₂⁰ with SMZ⁰ (regular H-bond) and SMZ^– (negative charge-assisted H-bond, ()CAHB) successively contributed most adsorption (pH 4–9). At weakly acidic pH, NH₂⁰ was partially protonated and electrostatic attraction between NH₃⁺ and SMZ^– occurred concurrently, but could be hindered by increased loading of SMZ⁰. Hydrophobic/ π–π interactions were not major mechanisms as phenanthrene and nitrobenzenes had little effect on SMZ adsorption. At alkaline pH, where SMZ^– and NH₂⁰ prevailed, adsorption was accompanied by the stoichiometric (∼1.0) proton exchange with water, leading to OH^– release and the formation of ()CAHB [SO₂N^–···H···NH₂]. The interaction and SMZ spatial distribution in the resin-phase were further confirmed by FTIR and Raman spectra. SMZ was uniformly adsorbed on external and interior surfaces. SMZ adsorption by PSA had low-interference from other coexistent matter, but high stability after multiple regenerations. The findings will guide new adsorbent designs for selectively removing target organics.