This work reports the first investigation on the use of EDDS as chelating agent in photoelectro-Fenton (PEF) treatment of water at near-neutral pH. As a case study, the removal of the antidepressant fluoxetine was optimized, using an electrochemical cell composed of an IrO2-based anode an air-diffusion cathode for in-situ H2O2 production. Electrolytic trials at constant current were made in ultrapure water with different electrolytes, as well as in urban wastewater (secondary effluent) at pH 7.2. PEF with Fe(III)-EDDS (1:1) complex as catalyst outperformed electro-Fenton and PEF processes with uncomplexed Fe(II) or Fe(III). This can be explained by: (i) the larger solubilization of iron ions during the trials, favoring the production of • OH from Fenton-like reactions between H2O2 and Fe(II)-EDDS or Fe(III)-EDDS, and (ii) the occurrence of Fe(II) regeneration from Fe(III)-EDDS photoreduction, which was more efficient than conventional photo-Fenton reaction with uncomplexed Fe(III). The greatest drug concentration decays were achieved at low pH, using only 0.10 mM Fe(III)-EDDS in a 1:1 molar ratio, although complete removal in wastewater was feasible only with 0.20 mM Fe(III)-EDDS due to the greater formation of • OH. The effect of the applied current and anode nature was rather insignificant. A progressive destruction of the catalytic complex was unveiled, whereupon the mineralization mainly progressed thanks to the action of • OH adsorbed on the anode surface. Despite the incomplete mineralization using BDD as the anode, a remarkable toxicity decrease was determined. Fluoxetine degradation yielded F − and NO3 − ions, along with several aromatic intermediates. These included two chloroorganics, as a result of the anodic oxidation of Cl − to active chlorine. A detailed mechanism for the Fe(III)-EDDS-catalyzed PEF treatment of fluoxetine in urban wastewater is finally proposed.