Both H2O2 generation and Fe3+/Fe2+ cycle play significant roles in electro-Fenton (EF) that produces hydroxyl radicals (center dot OH) to degrade refractory organic pollutants. Nevertheless, it is typically difficult to achieve O2 and Fe3+ reduction simultaneously due to their competition of cathode electrons. To address this challenge, herein, a novel tandem dual-system EF process was developed to realize efficient mineralization of sulfamethoxazole (SMX), in which a gas diffusion electrode (GDE) was used mainly for H2O2 accumulation (GDE-EF), while an activated carbon fiber (ACF) cathode was applied primarily for Fe2+ regeneration (ACF-EF). H2O2 accumulation by the GDE cathode was about 22 times higher than that by the ACF cathode. The ACF cathode significantly accelerated the conversion of Fe3+ to Fe2+, i.e., about 17.0 mg/L (30.6 %) of Fe2+ was maintained at 120 min in ACF-EF, much higher than 3.4 mg/L in GDE-EF (6.1 %). Up to 87.6% mineralization was achieved after 360 min of GDE+ACF-EF treatment. Effects of Fe2+ concentration, current density, pH, and SMX concentration on pollutant removal were investigated. Evolutions of inorganic ions and short-chain carboxylic acids were determined. Seven aromatic intermediates were identified by UPLC-QTOF-MS, while their ecotoxicity were also assessed. Finally, a reaction sequence for SMX mineralization was proposed.