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The development of cost-efficient and environmentally friendly technologies for the removal of cyanotoxins from water is crucial, given the increasingly frequent appearance of toxic cyanobacterial blooms. In this work, the application of catalytic wet peroxide oxidation (CWPO) promoted by natural magnetite for the removal of the highly toxic cyanotoxin cylindrospermopsin (CYN) has been investigated. A fixed-bed reactor packed with magnetite powder and granules was used to treat a continuous flow of CYN-bearing water. Experiments were carried out under ambient conditions and circumneutral pH (pH0 = 5). The effect of the main variables of the process, viz. magnetite load (8–14 g), feed flow rate (0.1–0.25 mL min−1), H2O2 dose (0.5–8 mg L−1) and initial CYN concentration (25–100 μg L−1), were systematically analyzed. CYN conversion values and kinetic constants were calculated to evaluate the feasibility of the catalytic system. The process was highly effective in the removal of the cyanotoxin, achieving up to 80% CYN conversion under optimized conditions (flow rate = 0.2 mL min−1, [H2O2]0 = 5 mg L−1, WFe3O4 = 14 g, pH0 = 5, T = 25 °C). It also showed reasonable activity (~55% CYN conversion) in two real samples (pond and river water). The decay on CYN conversion in these cases was mainly due to the scavenging of hydroxyl radicals by the co-existing species present in the matrices. Remarkably, the catalytic system showed high stability with limited iron leaching (the iron leached at the end of the experiments represented less than 0.2 wt.% of the catalyst's initial iron content) in all cases. Its stability was further confirmed in a long-term continuous experiment (60 h time on stream). Furthermore, the magnetite granules at the top layer of the packed bed avoided the loss of magnetite powder from the reactor, confirming the suitability of the system for continuous long-term application. [ABSTRACT FROM AUTHOR]