Sulfamethazine (SMZ) is one of the most widely used sulfonamides and is frequently detected in water resources, posing threats to human and ecological health. To address this concern, SMZ degradation was investigated using nanoscale zero-valent iron (nZVI) supported on an organo-montmorillonite (OMt) composite (nZVI/OMt), which was synthesized by reduction of Fe2+ with NaBH4, to activate persulfate (PS). Up to 97% degradation of 20 mg/L SMZ was achieved within 10 min using 1.5mM nZVI/OMt (mass/mass, 3/1) and 4mM persulfate at pH 6.8 and 25 degrees C. Experimental results indicated that SMZ degradation obeyed pseudo-first-order reaction kinetics, and the observed pseudo-first-order rate constant (k(obs)) in the nZVI/OMt-activated PS process was 1.5 times that for the nZVI-activated PS process. SMZ transformation was improved by increasing the PS concentration and temperature. Natural water constituents, such as Cl-, NO3-, and humic acid, slightly inhibited SMZ degradation, whereas SMZ transformation was significantly reduced by HCO3-. Electron paramagnetic resonance and radical scavenger experiments demonstrated that both (OH)-O-center dot and SO4 center dot- participated in SMZ degradation; however, SO4 center dot- was the dominant reaction mechanism. Degradation products were analyzed by UPLC-QTOF-MS and confirmed three reaction pathways: cleavage of the S-N bond; smiles-type rearrangement; and, oxidation of the aniline moiety. Overall, the experimental results suggest that nZVI/OMt-activated PS oxidation is an easy, lowcost, and efficient method for rapid remediation of SMZ-contaminated water.