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Sulfamethoxazole (SMX) is a typical antibiotic in the world, which is frequently detected in the aquatic environment. The current study was aimed to investigate the SMX degradation in secondary treated wastewater using potassium Ferrate [Fe(VI)]. The effects of various experimental conditions, EDTA and phosphate as chelating agents, and toxicity assessment were also considered. Secondary treated effluent was spiked with predefined SMX concentrations, and after desired reaction time with Fe(VI), residual SMX was measured using HPLC. Results indicated that SMX degradation by Fe(VI) was favored under acidic condition, where 90% of SMX degradation was achieved after 120 min. Fe(VI) and SMX reaction obeyed first-order kinetic; meantime, the SMX degradation rate under pH 3 was 7.6 times higher than pH 7. The presence of phosphate (Na 2 HPO 4 ) and EDTA declined SMX degradation, while Fe (III) effect was contradictory. In addition to promising demolition, 10% TOC removal was achieved. Eighteen major intermediates were identified using LC-MS/MS and the degradation pathways were suggested. Transformation products (TPs) were formed due to hydroxylation, bond cleavage, transformation after bond cleavage, and oxidation reactions. The ECOSAR analysis showed that some of the SMX oxidation products were toxic to aquatic organisms (fish, daphnia and green algae)., Supplementary Information: The online version contains supplementary material available at 10.1007/s40201-021-00769-9., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© Springer Nature Switzerland AG 2022.)